Xanthines in the 7th position with a benzyl acetic acid moiety

ABSTRACT

Substituted xanthines of formula ##STR1## in which A represents a radical of the formula ##STR2## in which R 3 , R 4 , R 6  and R 7  denote hydrogen, cycloalkyl, aryl having 6 to 10 carbon atoms, or denote straight-chain of branched alkyl or alkenyl, each of which is optionally substituted; T, V, X and Y are identical or different and denote an oxygen or sulphur atom; R 5  and R 8  are identical or different and denote hydrogen, halogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl or alkenyl in each case having up to 8 carbon atoms, optionally substituted or R 5  and R 8  denote aryl having 6 to 10 carbon atoms or a 5- to 7-membered aromatic, optionally benzo-fused heterocycle having up to 3 heteroatoms S, N and/or O, each of which is optionally substituted; L represents an oxygen or sulphur atom; R 2  represents mercapto, hydroxyl, straight-chain or branched alkoxy having up to 8 carbon atoms or the group of the formula ##STR3## in which R 13  denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms; R 14  denotes hydrogen, phenyl or a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms S, N and/or O; and R 15  denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atom, optionally substituted by hydroxyl, and their salts are prepared by reaction of the suitable unsubstituted xanthines with halogenomethylphenylacetic acids and subsequent reaction of the carboxylic esters or acids with phenylglycinolamine. The substituted xanthines are suitable as active compounds in medicaments, in particular in antiatherosclerotic medicaments.

The present invention relates to substituted xanthines, processes for their preparation and their use as medicaments, in particular as antiatherosclerotic medicaments.

It is known that raised blood levels of triglycerides (hypertriglyceridaemia) and cholesterol (hypercholesterolaemia) are associated with the genesis of atherosclerotic vascular wall changes and coronary heart diseases.

A distinctly increased risk of the development of coronary heart disorders is moreover present if these two risk factors occur in combination, accompanied, in turn, by an overproduction of apolipoprotein E-100. There is therefore still a great need to make available medicaments for the control of atherosclerosis and coronary heart diseases.

The present invention relates to substituted xanthines of the general formula (I) ##STR4## in which A represents a radical of the formula ##STR5## in which R³, R⁴, R⁶ and R⁷ are identical or different and denote hydrogen, cycloalkyl having 3 to 7 carbon atoms or aryl having 6 to 10 carbon atoms,

or denote straight-chain branched alkyl or alkenyl in each case having up to 8 carbon atoms, each of which is optionally substituted by halogen, hydroxyl or aryl having 6 to 10 carbon atoms,

T, V, X and Y are identical or different and denote an oxygen or sulphur atom,

R⁵ and R⁸ are identical or different and denote hydrogen, halogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl or alkenyl in each case having up to 8 carbon atoms, each of which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms, or by a 5- to 6-membered, aromatic, optionally benzo-fused heterocycle having up to 3 heteroatoms from the series X, N and/or O, by aryl having 6 to 10 carbon atoms, where the cycles for their part can be substituted identically or differently up to 3 times by a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and/or O, or by phenyl, benzyl, halogen, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 6 carbon atoms, or denote aryl having 6 to 10 carbon atoms or a 5- to 7-membered aromatic, optionally benzo-fused heterocycle having up to 3 heteroatoms from the series S, N and/or O, each of which is optionally substituted identically or differently up to 3 times by halogen, phenyl, trifluoromethyl, hydroxy, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 6 carbon atoms or by a group of the formula --(CO)_(a) --NR⁹ R¹⁰, in which

a denotes a number 0 or 1,

R⁹ and R¹⁰ are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl or acyl in each case having up to 5 carbon atoms,

D and E are identical or different and represent hydrogen, halogen, trifluoromethyl, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 6 carbon atoms,

R¹ represents hydrogen or cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkyl or alkenyl in each case having up to 8 carbon atoms, each of which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, phenyl or a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and/or O, or

represents phenyl or a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and/or O, where the ring systems are optionally substituted identically or differently up to 3 times by halogen, phenyl, trifluoromethyl or straight-chain or branched alkyl or alkoxy in each case having up to 5 carbon atoms, hydroxyl or a group of the formula --NR¹¹ R¹², in which

R¹¹ and R¹² have the meaning of R⁹ and R¹⁰ given above and are identical to or different from this,

L represents an oxygen or sulphur atom,

R² represents mercapto, hydroxyl, straight-chain or branched alkoxy having up to 8 carbon atoms or the group of the formula ##STR6## in which R¹³ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R¹⁴ denotes hydrogen, phenyl or a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and/or O,

R¹⁵ denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxyl, and their salts.

The substituted xanthines according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.

In the context of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention, which have a free carboxyl group. Those particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines, for example ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.

The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.

Heterocycle, if appropriate benzo-fused, in the context of the invention in general represents a saturated or unsaturated 5- to 7-membered, preferably 5- to 6-membered, heterocycle which can contain up to 3 heteroatoms from the series S, N and/or O. Examples which may be mentioned are: indolyl, quinolyl, benzo b!thiophene, benzo b!furanyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Quinolyl, furyl, pyridyl and thienyl are preferred.

Preferred compounds of the general formula (I) are those in which

A represents a radical of the formula ##STR7## in which R³, R⁴, R⁶ and R⁷ are identical or different and denote hydrogen, phenyl, cyclopropyl, cyclopentyl or cyclohexyl, or denote straight-chain or branched alkyl or alkenyl in each case having up to 6 carbon atoms, each of which is optionally substituted by fluorine, chlorine, bromine, hydroxyl or phenyl,

T, V, X and Y are identical or different and denote an oxygen or sulphur atom,

R⁵ and R⁸ are identical or different and denote hydrogen, fluorine, chlorine, bromine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or straight-chain or branched alkyl or alkenyl in each case having up to 6 carbon atoms, each of which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, naphthyl, phenyl, pyridyl, thienyl or furyl, which for their part can be substituted identically or differently up to 2 times by phenyl, benzyl, fluorine, chlorine, bromine, hydroxyl or straight or branched alkyl or alkoxy in each case having up to 4 carbon atoms, or

denote phenyl, pyridyl, thienyl or furyl, each of which is optionally substituted identically or differently up to 2 times by fluorine, chlorine, bromine, phenyl, trifluoromethyl, hydroxyl or straight-chain or branched alkyl or alkoxy in each case having up to 4 carbon atoms or a group of the formula --(CO)_(a) --NR⁹ R¹⁰, in which

a denotes a number 0 or 1,

R⁹ and R¹⁰ are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl or acyl in each case having up to 4 carbon atoms,

D and E are identical or different and represent hydrogen, fluorine, chlorine, bromine, trifluoromethyl, hydroxyl or straight-chain or branched alkyl or alkoxy in each case having up to 4 carbon atoms,

R¹ represents hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or straight-chain or branched alkyl or alkenyl in each case having up to 6 carbon atoms, each of which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyridyl or thienyl, or

represents phenyl, pyridyl, furyl or thienyl, each of which is optionally substituted identically or differently up to 2 times by fluorine, chlorine, bromine, phenyl, trifluoromethyl or straight-chain or branched alkyl or alkoxy in each case having up to 4 carbon atoms or a group of the formula --NR¹¹ R¹², in which

R¹¹ and R¹² have the meaning of R⁹ and R¹⁰ given above and are identical to or different from this,

L represents an oxygen or sulphur atom,

R² represents mercapto, hydroxyl, straight-chain or branched alkoxy having up to 6 carbon atoms or the group of the formula ##STR8## in which R¹³ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R¹⁴ denotes hydrogen, phenyl, pyridyl, furyl or thienyl,

R¹⁵ denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl, and their salts.

Particularly preferred compounds of the general (I) are those in which

A represents a radical of the formula ##STR9## in which R³, R⁴, R⁶ and R⁷ are identical or different and denote hydrogen, phenyl, cyclopropyl, cyclopentyl or cyclohexyl, or denote straight-chain or branched alkyl or alkenyl in each case having up to 5 carbon atoms, each of which is optionally substituted by fluorine, chlorine, bromine, hydroxyl or phenyl,

T, V, X and Y are identical or different and denote an oxygen or sulphur atom,

R⁵ and R⁸ are identical or different and denote hydrogen, fluorine, chlorine, bromine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or straight-chain or branched alkyl or alkenyl in each case having up to 5 carbon atoms, each of which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, thienyl or furyl, which for their part can be substituted identically or differently up to 2 times by phenyl, benzyl, fluorine, chlorine, bromine, hydroxyl or straight-chain or branched alkyl or alkoxy in each case having up to 3 carbon atoms, or

denote phenyl, pyridyl, thienyl or furyl, each of which is optionally substituted identically or differently up to 2 times by fluorine, chlorine, bromine, phenyl, trifluoromethyl, hydroxyl or straight-chain or branched alkyl or alkoxy in each case having up to 3 carbon atoms or a group of the formula --(CO)_(a) --NR⁹ R¹⁰, in which

a denotes a number 0 or 1,

R⁹ and R¹⁰ are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl or acyl in each case having up to 3 carbon atoms,

D and E are identical or different and represent hydrogen, fluorine, chlorine, bromine or trifluoromethyl,

R¹ represents hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or straight-chain or branched alkyl or alkenyl in each case having up to 5 carbon atoms, each of which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyridyl or thienyl, or represents phenyl, pyridyl, furyl or thienyl, each of which is optionally substituted identically or differently up to 2 times by fluorine, chlorine, bromine, phenyl, trifluoromethyl or straight-chain or branched alkyl or alkoxy in each case having up to 3 carbon atoms or a group of the formula --NR¹¹ R¹², in which

R¹¹ and R¹² have the meaning of R⁹ and R¹⁰ given above and are identical to or different from this,

L represents an oxygen or sulphur atom,

R² represents mercapto, hydroxyl, straight-chain or branched alkoxy having up to 5 carbon atoms or the group of the formula ##STR10## in which R¹³ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

R¹⁴ denotes hydrogen, phenyl, pyridyl or thienyl,

R¹⁵ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by hydroxyl, and their salts.

Very particularly preferred compounds of the general formula (I) are those in which

A represents a radical of the formula ##STR11## in which R³, R⁴, R⁶ and R⁷ are hydrogen, straight-chain or branched alkyl in each case having up to 4 carbon atoms,

T, V, X and Y are identical or different and denote an oxygen or sulphur atom,

R⁵ and R⁸ are identical or different and denote hydrogen, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclohexyl or straight-chain or branched alkyl or alkenyl in each case having up to 3 carbon atoms, each of which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, thienyl or furyl, which for their part can be substituted identically or differently up to 2 times by phenyl, benzyl, fluorine, chlorine, bromine, hydroxyl or straight-chain or branched alkyl or alkoxy in each case having up to 3 carbon atoms, or

denote phenyl, pyridyl, thienyl or furyl, each of which is optionally substituted identically or differently up to 2 times by fluorine, chlorine, bromine, phenyl, trifluoromethyl, hydroxyl or straight-chain or branched alkyl or alkoxy in each case having up to 3 carbon atoms or a group of the formula --(CO)_(a) --NR⁹ R¹⁰, in which

a denotes the number 0,

R⁹ and R¹⁰ are identical or different and denote hydrogen or straight-chain or branched alkyl in each case having up to 3 carbon atoms,

D and E are identical or different and represent hydrogen, fluorine, chlorine, bromine or trifluoromethyl,

R¹ represents hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms,

L represents an oxygen atom,

R² represents hydroxyl, straight-chain or branched alkoxy having up to 5 carbon atoms or the group of the formula ##STR12## in which R¹³ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

R¹⁴ denotes phenyl,

R¹⁵ denotes straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by hydroxyl, and their salts.

A process for the preparation of the compounds of the general formula (I) according to the invention has additionally been found, characterized in that first, by reaction of compounds of the general formula (II)

    A--H                                                       (II)

in which

A has the meaning given above, with compounds of the general formula (III) ##STR13## in which D, E, L and R¹ have the meaning given above,

R¹⁶ represents hydroxyl or halogen, preferably bromine, and

R^(2') represents straight-chain or branched alkoxy having up to 8 carbon atoms, in inert solvents and in the presence of bases and/or auxiliaries, the latter are converted into compounds of the general formula (Ia) ##STR14## in which A, D, E, L, R¹ and R^(2') have the meaning given above, and these are optionally hydrolysed (R² |OH), or, if appropriate, these acids are reacted with glycinols and glycinol derivatives of the general formula (IV) ##STR15## in which R¹³, R¹⁴ and R¹⁵ have the meaning given above, in inert solvents, if appropriate in the presence of bases and/or auxiliaries.

The process according to the invention can be illustrated by way of example by the following reaction scheme: ##STR16##

Suitable solvents for the process are customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or alcohols, for example methanol, ethanol, propanol, isopropanol, butanol, iso-butanol or tert-butanol, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoramide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide and tetrahydrofuran are preferred.

Bases which can be employed for the process are in general inorganic or organic bases. These preferably include alkali metal hydroxides, for example sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, for example barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkali metal or alkaline earth metal alkoxides such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or organic amines (trialkyl(C₁ -C₆)-amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo 2.2.2!octane (DABCO), 1,8-diazabicyclo 5.4.0!undec-7-ene(DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to employ as bases alkali metals such as sodium or their hydrides such as sodium hydride. Sodium hydride, potassium carbonate, triethylamine, pyridine and potassium tert-butoxide, DBU or DABCO are preferred.

In general, the base is employed in an amount from 0.05 to 10 mol, preferably from 1 to 2 mol, relative to 1 mol of the compound of the formula (II).

The processes according to the invention are in general carried out in a temperature range from -30° C. to +100° C., preferably from -10° C. to +60° C.

The processes according to the invention are in general carried out at normal pressure. However, it is also possible to carry out the processes at elevated pressure or at reduced pressure (e.g. in a range of from 0.5 to 5 bar).

The carboxylic acid esters are hydrolysed according to customary methods, by treating the esters with customary bases in inert solvents.

Suitable bases for the hydrolysis are the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides, for example sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate. Sodium hydroxide or potassium hydroxide or particularly preferably employed.

Suitable solvents for the hydrolysis are water or the organic solvents customary for hydrolysis. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulphoxide. Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferably used. It is also possible to employ mixtures of the solvents mentioned.

The hydrolysis can also be carried out using acids, for example trifluoroacetic acid, acetic acid, hydrochloric acid, hydrobromic acid, methanesulphonic acid, sulphuric acid or perchloric acid, preferably using trifluoroacetic acid.

The hydrolysis is in general carried out in a temperature range from 0° C. to +100° C., preferably from +20° C. to +80° C.

In general, the hydrolysis is carried out at normal pressure. However, it is also possible to work at reduced pressure or at elevated pressure (e.g. from 0.5 to 5 bar).

When carrying out the hydrolysis, the base is in general employed in an amount from 1 to 3 mol, preferably from 1 to 1.5 mol, relative to 1 mol of the ester. Molar amounts of the reactants are particularly preferably used.

Suitable solvents for the reaction with glycinols in this case are inert organic solvents which do not change under the reaction conditions. These preferably include ethers, such as diethyl ether or tetrahydrofuran, halogenohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoramide. It is also possible to employ mixtures of the solvents. Dichloromethane, tetrahydrofuran, acetone or dimethylformamide is particularly preferred.

Bases which can be employed here are in general inorganic or organic bases. These preferably include alkali metal hydroxides, for example sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, for example barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkali metal or alkaline earth metal alkoxides such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or organic amines (trialkyl(C₁ -C₆)amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo 2,2,2!octane (DABCO), 1,8-diaza-bicyclo 5.4.0!undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to employ as bases alkali metals such as sodium and their hydrides such as sodium hydride. Sodium and potassium carbonate and triethylamine are preferred.

The base is employed in an amount from 1 mol to 5 mol, preferably from 1 mol to 3 mol, relative to 1 mol of the appropriate carboxylic acid.

The reaction is in general carried out in a temperature range from 0° C. to 150° C., preferably from +20° C. to +110° C.

The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). In general, it is carried out at normal pressure.

The reaction with phenylglycinols can, if appropriate, also proceed via the activated stage of the acid halides, which can be prepared from the corresponding acids by reaction with thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide or oxalyl chloride.

The abovementioned bases can, if appropriate, also be employed as acid-binding auxiliaries.

Suitable auxiliaries are also dehydrating reagents. These include, for example, carbodiimides such as diisopropylcarbodiimide, dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate or propanephosphonic anhydride or iso-butyl chloroformate or benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate or diphenyl phosphoramidate or methane-sulphonyl chloride, if appropriate in the presence of bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide.

The acid-binding agents and dehydrating reagents are in general employed in an amount from 0.5 to 3 mol, preferably from 1 to 1.5 mol, relative to 1 mol of the corresponding carboxylic acids.

The compounds of the general formulae (III) and (IV) are known per se or can be prepared by customary methods.

The compounds of the general formula (II) are known or can be prepared by reacting, for example, the corresponding 1,3-substituted uracils with orthoformic acid esters or carbonyl chlorides and with aldehydes of the general formula (V)

    R.sup.17 --CHO                                             (V)

in which

R¹⁷ includes the meanings of R⁵ and/or R⁸ given above, in inert solvents and in the presence of a base.

Suitable solvents for the preparation are the abovementioned solvents. Ethanol, dichloromethane or dimethylformamide is preferred.

The reactions are carried out in a temperature range from 30° C. to 160° C., preferably at the boiling point of the respective solvent and normal pressure.

The aldehydes of the general formula (V) are known per se or can be prepared by customary methods.

The compounds of the general formula (Ia) are new and can be prepared by the process described above.

The compounds of the general formulae (I) and (Ia) according to the invention have an unforeseeable spectrum of pharmacological action.

They can be used as active compounds in medicaments for the reduction of changes to vascular walls and for the treatment of coronary heart disorders, cardiac insufficiency, brain function disorders, ischaemic brain disorders, apoplexy, circulatory disorders, microcirculation disorders and thromboses.

The proliferation of smooth muscle cells furthermore plays a decisive part in the occlusion of vessels. The compounds according to the invention are suitable for inhibiting this proliferation and thus for preventing atherosclerotic processes.

The compounds according to the invention are distinguished by a lowering of ApoB-100-associated lipoproteins (VLDL and its degradation products, e.g. LDL), of ApoB-100, of triglycerides and of cholesterol. They thus have valuable and superior pharmacological properties in comparison with the prior art.

The action of the compounds according to the invention surprisingly consists first in a reduction or complete inhibition of the formation and/or of the release of ApoB-100-associated lipoproteins from liver cells, which results in a lowering of the VLDL plasma level. This VLDL-lowering must be accompanied by a lowering of the plasma levels of ApoB-100, LDL, triglycerides and of cholesterol; thus several of the abovementioned risk factors which are involved in vascular wall changes are simultaneously lowered.

The compounds according to the invention can therefore be employed for the prevention and treatment of atherosclerosis, obesity, pancreatitis and constipation.

1. INHIBITION OF THE RELEASE OF APOB-100-ASSOCIATED LIPOPROTEINS

The test for detecting inhibition of the release of ApoB-100-associated lipoproteins from liver cells was carried out in vitro using cultured liver cells, preferably using cells of the human line HepG2. These cells are grown under standard conditions in medium for the culture of eucaryotic cells, preferably in RPMI 1640 using 10% foetal calf serum. HepG2 cells synthesize and secrete into the culture supernatant ApoB-100-associated lipoprotein particles which in principle are synthesized in a similar manner to the VLDL and LDL particles which are to be found in the plasma.

These particles can be detected using an immunoassay for human LDL. This immunoassay is carried out using antibodies which have been induced in the rabbit against human LDL under standard conditions. The anti-LDL antibodies (rabbit anti-LDL-Ab) were purified by affinity chromatography on an immunosorbent using human LDL. These purified rabbit anti-LDL Ab are adsorbed on the surface of plastic. Expediently, this adsorption is carried out on the plastic surface of microtitre plates having 96 wells, preferably on MaxiSorp plates. If ApoB-100-associated particles are present in the supernatant of Hep-G2 cells, these can bind to the insolubilized rabbit anti-LDL Ab, and an immune complex is formed which is bound to the plastic surface. Unbound proteins are removed by washing. The immune complex located on the plastic surface is detected using monoclonal antibodies which have been induced against human LDL according to standard conditions and purified. These antibodies were conjugated with the enzyme peroxidase. Peroxidase converts the colourless substrate TMB into a coloured product in the presence of H₂ O₂. After acidification of the reaction mixture using H₂ SO₄, the specific light absorption at 450 mn is determined, which is a measure of the amount of ApoB-100-associated particles which have been secreted into the culture supernatant by the HepG2 cells.

Surprisingly, the compounds according to the invention inhibit the release of the ApoB-100-associated particles. The IC₅₀ value indicates at which substance concentration the light absorption is inhibited by 50% in comparison with the control (solvent control without substance).

                  TABLE 1                                                          ______________________________________                                         Example No.  ApoB IC.sub.50   nM!                                              ______________________________________                                         112          4.0                                                               113          58.0                                                              114          39.0                                                              115          240.0                                                             117          3.0                                                               118          7.0                                                               119          11.0                                                              120          28.0                                                              121          36.0                                                              122          48.0                                                              123          8.0                                                               126          41.0                                                              129          34.0                                                              130          25.0                                                              131          135.0                                                             132          743.0                                                             133          5.0                                                               136          23.0                                                              137          124.0                                                             138          403.0                                                             139          90.0                                                              140          10.0                                                              143          11.0                                                              146          6.0                                                               149          9.0                                                               151          34.0                                                              152          169.0                                                             154          3.0                                                               155          2.0                                                               156          25.0                                                              157          8.0                                                               158          2.0                                                               159          25.0                                                              160          5.0                                                               163          131.0                                                             164          12.0                                                              167          19.0                                                              168          16.0                                                              169          3.0                                                               170          16.0                                                              171          2.0                                                               172          1.0                                                               l74          5.0                                                               175          32.0                                                              176          19.0                                                              178          64.0                                                              179          5.0                                                               180          5.0                                                               181          10.0                                                              182          12.0                                                              183          10.0                                                              184          24.0                                                              185          29.0                                                              188          23.0                                                              189          31.0                                                              190          86.0                                                              191          14.0                                                              192          8.0                                                               193          62.0                                                              194          8.0                                                               195          5.0                                                               196          61.0                                                              197          43.0                                                              198          5.0                                                               199          5.0                                                               200          24.0                                                              201          11.0                                                              202          9.0                                                               203          63.0                                                              204          16.0                                                              207          40.0                                                              211          9.0                                                               212          8.0                                                               215          3.0                                                               216          34.0                                                              217          11.0                                                              218          8.0                                                               219          5.0                                                               220          16.0                                                              223          4.0                                                               224          4.0                                                               225          4.0                                                               226          11.0                                                              227          40.0                                                              ______________________________________                                    

2. DETERMINATION OF VLDL SECRETION IN VIVO IN THE HAMSTER

The effects of the test substances on VLDL secretion in vivo is investigated in the hamster. To do this, golden hamsters are anaesthetized with Ketavet (83 mg/kg s.c.) and Nembutal (50 mg/kg i.p.) after premedication with atropine (83 mg/kg s.c.). When the animals have become reflex-free, the jugular vein is exposed and cannulated. 0.25 ml/kg of a 20% strength solution of Triton WR 1339 in physiological saline solution is then administered. This detergent inhibits the lipoprotein lipase and thus leads to an increase in the triglyceride level as a result of lack of catabolism of secreted VLDL particles. This triglyceride increase can be used as a measure of the VLDL secretion rate. Blood is taken from the animals before and one and two hours after administration of the detergent by puncture of the retroorbital venous plexus. The blood is incubated for two hours at room temperature, then overnight at 4° C. in order to finish clotting completely. It is then centrifuged at 10,000 g for 5 minutes. The triglyceride concentration in the serum thus obtained is determined with the aid of a modified commercially available enzyme test (Merckotest® triglyceride No. 14354). 100 μl of serum are mixed with 100 μl of test reagent in 96-hole plates and incubated at room temperature for 10 minutes. The optical density is then determined at a wavelength of 492 nM in an automatic plate-reading apparatus (SLT spectra). Serum samples having too high a triglyceride concentration are diluted with physiological saline solution. The triglyceride concentration contained in the samples is determined with the aid of a standard curve measured in parallel. Test substances are administered in this model either intravenously immediately before administration of the detergent or orally or subcutaneously before initiation of the anaesthesia.

                  TABLE 2                                                          ______________________________________                                                    Triton hamster Triton hamster                                       Example    % TG inhibition                                                                               % CH inhibition                                      No.        2 h after substance                                                                           2 h after substance                                  ______________________________________                                         129        25% at 6 mg/kg i.v.                                                                           25% at 6 mg/kg i.v.                                  ______________________________________                                    

3. INHIBITION OF INTESTINAL TRIGLYCERIDE ABSORPTION IN VIVO (RATS)

The substances which are to be investigated for their triglyceride absorption-inhibiting action in vivo are administered orally to male Wistar rats having a body weight of between 170 and 230 g. For this purpose, the animals are divided into groups of 6 animals 18 hours before administration of the substance and the feed is then withdrawn from them. Drinking water is available to the animals ad libitum. The animals of the control groups receive an aqueous tragacanth suspension or a tragacanth suspension which contains olive oil. The tragacanth-olive oil suspension is prepared using an Ultra-Turrax. The substances to be investigated are suspended directly before substance administration in a corresponding tragacanth-olive oil suspension, also using an Ultra-Turrax.

Before stomach tube application, blood is taken from each rat by puncture of the retroorbital venous plexus to determine the basal serum triglyceride content. The tragacanth suspension, the tragacanth-olive oil suspensions without substance (control animals) and the substances suspended in a corresponding tragacanth-olive oil suspension are then administered to the fasting animals using a stomach tube. Further taking of blood for the determination of the postprandial serum triglyceride rise is carried out, as a rule, 1,2 and 3 hours after stomach tube application.

The blood samples are centrifuged and, after recovering the serum, the triglycerides are determined photometrically using an EPOS analyzer 5060 (Eppendorf Geratebau, Netheler & Hinz GmbH, Hamburg). The triglycerides are determined by fully enzymatic means using a commercially available UV test.

The postprandial serum triglyceride increase is determined by subtraction of the triglyceride preliminary value of each animal from its corresponding postprandial triglyceride concentrations (1,2 and 3 hours after administration).

The differences (in mmol/l) at each time 1, 2 and 3 hours) are averaged in the groups, and the average values of the serum triglyceride increase (ΔTG) of the substance-treated animals are compared with the animals which only received the tragacanth-oil suspension.

Likewise, the serum triglyceride course of the control animals which received only tragacanth is calculated. The substance effect at each time (1, 2 or 3 hours) is determined as follows and given in Δ% of the oil-loaded control. ##EQU1##

Effect of 10 mg of test substance/kg of body weight p.o. on the triglyceride increase (Δ%) 2 h after a triglyceride loading in the serum of fasting rats. The serum triglyceride increase of fat-loaded control animals based on the serum triglyceride level of tragacanth control animals corresponds to 100%. n=6 animals per group.

                  TABLE 3                                                          ______________________________________                                         Example    Absorption ED.sub.50  or % inhibition                               No.        (mg/kg p.o.)                                                        ______________________________________                                         112        3 mg/kg                                                             114        <2 mg/kg                                                            117        3 mg/kg                                                             123        2 mg/kg                                                             129        20 mg/kg                                                            130        5 mg/kg                                                             133        2 mg/kg                                                             136        2 mg/kg                                                             140        >3 mg/kg                                                            143        >3 mg/kg                                                            146        >3 mg/kg                                                            149        >3 mg/kg                                                            151        6 mg/kg                                                             154        <2 mg/kg                                                            157        >2 mg/kg                                                            160        3 mg/kg                                                             167        >2 mg/kg                                                            169        2 mg/kg                                                             174        <2 mg/kg                                                            178        3 mg/kg                                                             179        >3 mg/kg                                                            182        2 mg/kg                                                             191        >>3 mg/kg                                                           197        3 mg/kg                                                             201        >3 mg/kg                                                            227        >6 mg/kg                                                            ______________________________________                                    

Statistical assessment was carried out using student3 s t test after prior checking of the variances for homogeneity.

Substances which at one point statistically significantly (p<0.05) reduce the postprandial serum triglyceride increase by at least 30%, compared with the untreated control group, are regarded as pharmacologically active.

4. INHIBITION OF VLDL SECRETION IN VIVO (RAT)

The action of the test substances on VLDL secretion is also investigated in the rat. To do this, 500 mg/kg of body weight (2.5 ml/kg) of Triton WR-1339, dissolved in physiological saline solution, are administered to rats intravenously in the tail vein. Triton WR-1339 inhibits lipoprotein lipase and thus leads through inhibition of VLDL catabolism to an increase in the triglyceride and cholesterol level. These increases can be used as a measure of the VLDL secretion rate.

Blood is taken from the animals before and one and two hours after administration of the detergent by puncture of the retroorbital venous plexus. The blood is incubated at room temperature for 1 h for clotting and the serum is recovered by centrifugation at 10,000 g for 20 s. The triglycerides are then determined photometrically at a wavelength of 540 nm by means of a commercially available coupled enzyme test (Sigma Diagnostics®, No. 339). Measurement is carried out with the aid of a likewise coupled enzyme test (Boehringer Mannheim®, No. 1442350) at a wavelength of 546 nm. Samples with triglyceride or cholesterol concentrations which exceed the measuring range of the methods are diluted with physiological saline solution. The respective serum concentrations are determined with the aid of standard series measured in parallel. Test substances are administered orally, intravenously or subcutaneously immediately after the Triton injection.

                  TABLE 4                                                          ______________________________________                                                         Triton rat                                                                     % TG inhibition (p.o.)                                         Ex. No.         2 h after substance                                            ______________________________________                                         112             17.0% at 3 mg/kg (n.s.)                                        114             14.1% at 3 mg/kg (n.s.)                                        117             25% at 3 mg/kg (n.s.)                                          130             36% at 20 mg/kg                                                136             28% at 3 mg/kg                                                 154             (-4%) at 3 mg/kg (n.s.)                                        157             11.3% at 3 mg/kg                                               169             59.4% at 10 mg/kg                                              169             41% at 5 mg/kg                                                 169             28% at 3 mg/kg                                                 175             9.8% at 3 mg/kg (n.s.)                                         176             6.2% at 3 mg/kg (n.s.)                                         227             (-8%) at 3 mg/kg (n.s.)                                        ______________________________________                                    

The invention additionally relates to the combination of substituted xanthines of the general formula (I) with a glucosidase and/or amylase inhibitor for the treatment of familial hyperlipidaemias, obesity (adiposity) and diabetes mellitus. Glucosidase and/or amylase inhibitors in the context of the invention are, for example, acarbose, adiposine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose, MDL-73945, tendamistat, AI-3688, trestatin, pradimilin-Q and salbostatin.

The combination of acarbose, miglitol, emiglitate or voglibose with one of the abovementioned compounds of the general formula (I) according to the invention is preferred.

The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. In this context, the therapeutically active compound should in each case be present in a concentration of approximately 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.

The formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, if water is used as a diluent organic solvents can optionally be used as auxiliary solvents.

Administration is carried out in a customary manner, preferably orally or parenterally, in particular perlingually or intravenously.

In the case of parenteral administration, solutions of the active compound can be employed using suitable liquid excipient materials.

In general, it has proved advantageous in the case of intravenous administration to administer amounts of approximately 0.001 to 1 mg/kg, preferably approximately 0.01 to 0.5 mg/kg of body weight to achieve effective results, and in the case of oral administration the dosage is approximately 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.

In spite of this, it may, if appropriate, be necessary to depart from the amounts mentioned, namely depending on the body weight or on the type of administration route, on the individual behaviour towards the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus, in some cases it may be adequate to manage with less than the abovementioned minimum amounts, while in other cases the upper limit mentioned has to be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into several individual doses over the course of the day.

ABBREVIATIONS USED

    ______________________________________                                         Ac    =       acetyl                                                           bs    =       broad singlet                                                    Bn    =       benzyl                                                           Bz    =       benzoyl                                                          CI    =       chemical ionization                                              cDec  =       cyclodecyl                                                       cDodec                                                                               =       cyclododecyl                                                     cHept =       cycloheptyl                                                      cHex  =       cyclohexyl                                                       cNon  =       cyclononyl                                                       cOct  =       cyclooctyl                                                       cPent =       cyclopentyl                                                      cPr   =       cyclopropyl                                                      cUndec                                                                               =       cycloundecyl                                                     d     =       doublet                                                          DCC   =       dicyclohexylcarbodiimide                                         DCCI  =       N'-(3-dimethylaminopropyl)-N'-ethylcarbodiimide                  dd    =       doublet doublets                                                 DDQ   =       2,3-dichloro-5,6-dicyano-1,4-benzoquinone                        dia   =       diastereomer                                                     DMAP  =       4-(N,N-dimethylamino)pyridine                                    DMF   =       N,N-dimethylformamide                                            DMSO  =       dimethyl sulphoxide                                              EI    =       electron impact ionization                                       ent   =       enantiomer                                                       Et    =       ethyl                                                            FAB   =       fast atom bombardment                                            HOBT  =       1-hydroxy-1H-benzotriazole                                       Hz    =       Hertz                                                            iBu   =       isobutyl                                                         iPr   =       isopropyl                                                        m     =       multiplet                                                        Me    =       methyl                                                           Mes   =       mesyl                                                            NBS   =       bromosuccinimide                                                 nBu   =       normal benzyl                                                    nPr   =       normal propyl                                                    Ph    =       phenyl                                                           PPA   =       polyphosphoric acid                                              pTol  =       para-tolyl                                                       pTos  =       para-tosyl                                                       rac   =       racemate                                                         RT    =       room temperature                                                 s     =       singlet                                                          sBu   =       secondary butyl                                                  tBu   =       tertiary butyl                                                   t     =       triplet                                                          TFA   =       trifluoroacetic acid                                             THF   =       tetrahydrofuran                                                  TMS   =       tetramethylsilane                                                ______________________________________                                    

SOLVENT MIXTURES USED

    ______________________________________                                         Petroleum ether:acetone                                                                              =     1:1    (A)                                         Petroleum ether:ethyl acetate                                                                        =     20:1   (B)                                         Petroleum ether:ethyl acetate                                                                        =     10:1   (C)                                         Petroleum ether:ethyl acetate                                                                        =     5:1    (D)                                         Petroleum ether:ethyl acetate                                                                        =     3:1    (E)                                         Petroleum ether:ethyl acetate                                                                        =     2:1    (F)                                         Petroleum ether:ethyl acetate                                                                        =     1:1    (G)                                         Petroleum ether:ethyl acetate                                                                        =     1:2    (H)                                         Dichloromethane (100%)                                                                               =            (I)                                         Dichloromethane:methanol                                                                             =     50:1   (J)                                         Dichloromethane:methanol                                                                             =     20:1   (K)                                         Dichloromethane:methanol                                                                             =     10:1   (L)                                         Dichloromethane:ethyl acetate                                                                        =     1:1    (M)                                         Dichloromethane:ethanol                                                                              =     50:1   (N)                                         Ethyl acetate:methanol                                                                               =     10:1   (O)                                         Toluene (100%)        =            (P)                                         Toluene:ethyl acetate =     1:1    (Q)                                         Toluene:ethyl acetate =     8:1    (R)                                         Toluene:ethyl acetate =     9:1    (S)                                         Petroleum ether:ethyl acetate                                                                        =     4:1    (T)                                         ______________________________________                                    

ADDITIONS

The following marks are valid for all tables which follow: *=EI #=CI

EXAMPLE I (Method A)

1,3-Dimethyl-8-(4-methyl)phenyl-xanthine ##STR17##

8.5 g (50 mmol) of 5,6-diamino-1,3-dimethyluracil hydrate were dissolved in ethanol (180 ml) under reflux. A solution of 6.0 g (50 mmol) of p-tolylaldehyde and 4.5 g of acetic acid in ethanol (50 ml) was added to this solution. The mixture was heated under reflux for 1 hour, cooled to room temperature and filtered with suction. The crystals were washed with diethyl ether.

The crystals thus obtained were initially introduced and treated with 36.6 g (210 mmol) of diethyl azodicarboxylate. The mixture was warmed at 90° C. for 5 min, a solid being precipitated. The solution was cooled to room temperature and diluted with ethanol (100 ml). The solid which was precipitated was filtered off with suction, washed with diethyl ether and dried in vacuo.

Yield 10.9 g (81%);

R_(f) =0.56 (dichloromethane:methanol, 20:1);

M.p.=>240° C.;

Mass (calculated) for C₁₄ H₁₄ N₄ O₂ =270.30, mass spectrum (EI, rel. intensity) 270 (100%);

¹ H NMR (200 MHz, pyridine-D₅) δ8.29 (d, J=8.62 Hz, 2 H), 7.33 (d, J=7.89 Hz, 2 H), 4.98 (bs, 1 H), 3.72 (s, 3 H), 3.53 (s, 3 H), 2.29 (s, 3 H).

EXAMPLE II (Method B)

1,3-Dimethyl-8- 1-(3-chlorophenyl)methyl!xanthine ##STR18##

11.94 g (70 mmol) of 3-chlorophenylacetic acid were dissolved in 100 ml of dichloromethane, treated with a drop of DMF and cooled to 0° C. 8.74 g (73.5 mmol) of thionyl chloride were slowly added to this solution and it was stirred until the evolution of gas was complete (about 1 h), the reaction mixture being allowed to warm to room temperature.

11.91 g (70 mmol) of 5,6-diamino-1,3-dimethyluracil hydrate were initially introduced into 1M NaOH (150 ml) and water (350 ml) and warmed to 45° C. until a homogeneous solution resulted. This solution was cooled to room temperature and the acid chloride solution (see above) was added with vigorous stirring. The mixture was stirred at room temperature for a further 16 h. The solid which was precipitated was filtered off with suction and washed with water.

This solid was suspended in methanol (400 ml) and heated under reflux for 1 h with 4M NaOH (400 ml). After cooling to room temperature, the solution was acidified to pH 3 using conc. HCl, the desired product being precipitated. The solid which was precipitated was filtered off with suction, washed with water and methanol and dried in a recirculating air cabinet.

Yield 17.1 g (80%);

R_(f) =0.57 (dichloromethane:methanol, 10:1);

M.p.=>240° C;

Mass (calculated) for C₁₄ H₁₃ ClN₄ O₂ =304.74, mass spectrum (EI, rel. intensity) 304 (100%);

¹ H NMR (200 MHz, trifluoroacetic acid-D₁) δ7.36-7.30 (m, 3 H), 7.20 (m, 1 H), 4.50 (s, 2 H), 3.74 (s, 3 H), 3.52 (s, 3 H).

EXAMPLE III (Method C)

1,3-Diethylxanthine ##STR19##

5.0 g (25 mmol) of 5,6-diamino-1,3-diethyluracil and 475 mg (2.5 mmol) of p-toluenesulphonic acid were dissolved in trimethyl orthoformate (50 ml). The mixture was heated at reflux for 1 hour, then cooled and filtered with suction. As a polar impurity was present, the substance was purified by chromatography on silica gel:

Yield 3.5 g (67%);

R_(f) =0.15 (dichloromethane:methanol, 20:1);

M.p.=218°-220° C.;

Mass (calculated) for C₉ H₁₂ N₄ O₂ =208.23, mass spectrum (EI, rel intensity) 208 (100%);

¹ H NMR (200 MHz, DMSO-D₆)δ13.55 (bs, 1 H), 8.05 (s, 1 H), 4.04 (q, J=7.07 Hz, 2 H), 3.93 (q, J=7.02 Hz, 2 H), 1.23 (t, J=7.03 Hz, 3 H), 1.13 (t, J=7.01 Hz, 3 H).

The compounds shown in Table I were prepared by the methods shown there:

                                      TABLE 1                                      __________________________________________________________________________      ##STR20##                                                                                                            M.p.            Yield                   Example No.                                                                           R.sup.4                                                                           R.sup.3                                                                            R.sup.5       T  V  R.sub.f *                                                                           (°C.)                                                                       Method                                                                              Mass spectrum                                                                         (% of                   __________________________________________________________________________                                                            theory)                 IV     CH.sub.3                                                                          CH.sub.3                                                                           CH.sub.3      O  O  0.57(L)                                                                             >240                                                                               C    *194(100%)                                                                            50                      V      CH.sub.3                                                                          CH.sub.3                                                                           C.sub.2 H.sub.5                                                                              O  O  0.56(K)                                                                             >240                                                                               C    *208(100%)                                                                            46                      VI     CH.sub.3                                                                          CH.sub.3                                                                           cPro          O  O  0.35(K)                                                                             >240                                                                               A    *220(100%)                                                                            47                      VII    CH.sub.3                                                                          CH.sub.3                                                                           CH.sub.2 cHex O  O  0.61(L)                                                                              238                                                                               B    *276(40%)                                                                             72                                                                      194(100%)                      VIII   CH.sub.3                                                                          CH.sub.3                                                                            ##STR21##    O  O  0.80(L)                                                                             >240                                                                               B    276(100%)                                                                             47                      IX     CH.sub.3                                                                          CH.sub.3                                                                            ##STR22##    O  O  0.67(K)                                                                             >240                                                                               A    *270(100%)                                                                            82                      X      CH.sub.3                                                                          CH.sub.3                                                                            ##STR23##    O  O  0.86(L)                                                                             >240                                                                               A    *270(100%)                                                                            79                      XI     CH.sub.3                                                                          CH.sub.3                                                                            ##STR24##    O  O  0.80(L)                                                                             >240                                                                               A    *284(100%)                                                                            69                      XII    CH.sub.3                                                                          CH.sub.3                                                                            ##STR25##    O  O  0.85(L)                                                                             >240                                                                               B    *332(100%)                                                                            73                      XIII   CH.sub.3                                                                          CH.sub.3                                                                            ##STR26##    O  O  0.77(L)                                                                             >240                                                                               A    *290(100%)                                                                            73                      XIV    CH.sub.3                                                                          CH.sub.3                                                                            ##STR27##    O  O  0.75(L)                                                                             >240                                                                               A    *324(100%)                                                                            69                      XV     CH.sub.3                                                                          CH.sub.3                                                                            ##STR28##    O  O  0.80(L)                                                                             >240                                                                               A    *286(100%)                                                                            76                      XVI    CH.sub.3                                                                          CH.sub.3                                                                            ##STR29##    O  O  --   >240                                                                               A    *299(100%)                                                                            77                      XVII   CH.sub.3                                                                          CH.sub.3                                                                            ##STR30##    O  O       >250                                                                               A    #328(100%)                                                                            81                      XVIII  CH.sub.3                                                                          CH.sub.3                                                                            ##STR31##    O  O  0.33(K)                                                                             >240                                                                               A    257(100%)                                                                             58                      XIX    CH.sub.3                                                                          CH.sub.3                                                                            ##STR32##    O  O  0.26(K)                                                                             >240                                                                               A    *257(100%)                                                                            66                      XX     CH.sub.3                                                                          CH.sub.3                                                                            ##STR33##    O  O  0.15(K)                                                                             >240                                                                               A    *258(100%)                                                                            21                      XXI    CH.sub.3                                                                          CH.sub.3                                                                            ##STR34##    O  O  0.40(K)                                                                             >240                                                                               A    *262(100%)                                                                            80                      XXII   CH.sub.3                                                                          CH.sub.3                                                                            ##STR35##    O  O       >240                                                                               A           88                      XXIII  CH.sub.3                                                                          CH.sub.3                                                                            ##STR36##    O  O  0.30(K)                                                                             >240                                                                               A    276(100%)                                                                             78                      XXIV   CH.sub.3                                                                          CH.sub.3                                                                            ##STR37##    O  O  0.38(K)                                                                             >240                                                                               A    276(100%)                                                                             75                      XXV    CH.sub.3                                                                          CH.sub.3                                                                            ##STR38##    O  O  0.54(K)                                                                             >240                                                                               A    341(100%)                                                                             83                      XXVI   CH.sub.3                                                                          CH.sub.3                                                                            ##STR39##    O  O  0.69(K)                                                                             >240                                                                               A    283(100%)                                                                             70                      XXVII  CH.sub.3                                                                          CH.sub.3                                                                            ##STR40##    O  O  0.68(L)                                                                             >240                                                                               B    *284(100%)                                                                            68                      XXVIII CH.sub.3                                                                          CH.sub.3                                                                            ##STR41##    O  O  0.68(L)                                                                             >240                                                                               B    *284(100%)                                                                            64                      XXIX   CH.sub.3                                                                          CH.sub.3                                                                            ##STR42##    O  O  0.28(K)                                                                             >240                                                                               B    *284(100%)                                                                            64                      XXX    CH.sub.3                                                                          CH.sub.3                                                                            ##STR43##    O  O  0.78(L)                                                                             >240                                                                               B    *346(100%)                                                                            47                      XXXI   CH.sub.3                                                                          CH.sub.3                                                                            ##STR44##    O  O  0.57(L)                                                                             >240                                                                               B    *304(100%)                                                                            71                      XXXII  CH.sub.3                                                                          CH.sub.3                                                                            ##STR45##    O  O  0.64(L)                                                                             >240                                                                               B    *288(100%)                                                                            49                      XXXIII CH.sub.3                                                                          CH.sub.3                                                                            ##STR46##    O  O  0.61(L)                                                                             >240                                                                               B    *300(100%)                                                                            64                      XXXIV  CH.sub.3                                                                          CH.sub.3                                                                            ##STR47##    O  O  0.64(K)                                                                             >240                                                                               B    *300(100%)                                                                            66                      XXXV   CH.sub.3                                                                          CH.sub.3                                                                            ##STR48##    O  O  0.27(K)                                                                             >240                                                                               B    *300(100%)                                                                            23                      XXXVI  CH.sub.3                                                                          CH.sub.3                                                                            ##STR49##    O  O  0.74(K)                                                                             143-45                                                                             A    *346(100%)                                                                             7                      XXXVII C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    CH.sub.3      O  O  0.83(K)                                                                             231-33                                                                             C    *222(100%)                                                                            54                      XXXVIII                                                                               C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                              O  O  0.71(K)                                                                             193-94                                                                             C    *236(100%)                                                                            67                      XXXIX  C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    cPro          O  O  0.69(L)                                                                             217-18                                                                             A    #249(100%)                                                                            39                      XL     C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                     ##STR50##    O  O  0.76(L)                                                                             >240                                                                               A    #299(100%)                                                                            70                      XLI    C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                     ##STR51##    O  O  0.67(L)                                                                             >240                                                                               A    #291(100%)                                                                            82                      XLII   CH.sub.3                                                                          CH.sub.3                                                                           CH.sub.3      S  O  0.30(K)                                                                             >240                                                                               C    *210(100%)                                                                            51                      XLIII  CH.sub.3                                                                          CH.sub.3                                                                           C.sub.2 H.sub.5                                                                              S  O  0.62(K)                                                                             >240                                                                               C    *224(100%)                                                                            78                      XLIV   CH.sub.3                                                                          CH.sub.3                                                                            ##STR52##    S  O  0.79(K)                                                                             >240                                                                               A    *278(100%)                                                                            51                      XLV    CH.sub.3                                                                          CH.sub.3                                                                            ##STR53##    S  O  0.80(K)                                                                             >240                                                                               A    *286(100%)                                                                            59                      __________________________________________________________________________

EXAMPLE XLVI

Methyl 2-(R&S)-phenyl-2-(4-methyl)phenylacetate ##STR54##

21.0 g (100 mmol, Apin) of 2-phenyl-1-(4-methyl)phenyl-1-oxoethane and 38.8 g (120 mmol) of iodobenzene diacetate were dissolved in 300 ml of trimethyl orthoformate. 19.6 g of conc. sulphuric acid were added to this solution, and the solution was warmed at 60° C. for 6 hours. The solution was cooled to room temperature, diluted with water (100 ml) and extracted with diethyl ether. The combined organic phases were dried over sodium sulphate and concentrated in a rotary evaporator. The residue was purified by column chromatography.

Yield 13.1 g (55%);

R_(f) =0.33 (petroleum ether:ethyl acetate, 20:1);

Mass (calculated for C₁₆ H₁₆ O₂ =240.30, mass spectrum (FAB, rel. intensity) 241 (25%), 181 (100%);

¹ H NMR (200 MHz, CDCl₃)δ7.3-7.10 (m, 9 H), 4.99 (s, 1 H), 3.73 (s, 3 H), 2,31 (s, 3 H).

EXAMPLE XLVII

tert-Butyl 2-cyclopentyl-2-(4-methylphenyl)acetate ##STR55##

33.5 g (0.3 mol) of potassium tert-butoxide are initially introduced into 100 ml of anhydrous DMF at 0° C., and 51.6 g (0.25 mol) of tert-butyl 4-methylphenyl-acetate in 250 ml of anhydrous DMF are added dropwise. The mixture is stirred at 0° C. for 30 min and 32.2 ml (0.3 mol) of cyclopentyl bromide in 150 ml of anhydrous DMF are added dropwise at 5°-15° C. and it is stirred at 25° C. for 20 h. After concentrating, the residue is partitioned between water and diethyl ether, and the ether phase is dried over sodium sulphate and concentrated. The product crystallizes out.

Yield: 67 g (97.5% of theory)

Melting point: 51°-53° C.

The compounds of Table II are prepared analogously to the procedure of Example XLVII:

                  TABLE II                                                         ______________________________________                                          ##STR56##                                                                     Ex. No.     R.sup.1     R.sup.18  R.sub.f *                                    ______________________________________                                         XLIII       (R&S) iPr   CH.sub.3  0.86 (S)                                     IL          (R&S) iBu   tBu       0.84 (R)                                     L           (R&S) cPent CH.sub.3  0.59 (C)                                     LI          (R&S) cHex  CH.sub.3  0.38 (B)                                     LII         (R&S) cHex  tBu       0.71 (P)                                     LIII        (R&S) cHept CH.sub.3  0.57 (P)                                     LIV         (R&S) cHept tBu       0.32 (P)                                     ______________________________________                                    

EXAMPLE LV

tert-butyl 2-(4-bromomethyl-phenyl)-2-cyclopentyl-acetate ##STR57##

27.4 g (0.1 mol) of the compound from Example XLVII are dissolved in 200 ml of tetrachloromethane and heated to boiling. After addition of 0.82 g of azobisisobutyronitrile, 18.7 g (0.105 mol) of N-bromosuccinimide are added in portions and the mixture is then refluxed for 1 h, cooled to 0° C. and succinimide is filtered off. After concentrating the filtrate, the product precipitates out. It is washed with petroleum ether (40:60) and dried.

Yield: 20 g (57% of theory);

M.p.: 73°-76° C.

The compounds of Table III are prepared analogously to the procedure of Example LV:

                  TABLE III                                                        ______________________________________                                          ##STR58##                                                                     Ex. No.                                                                               R.sup.1    R.sup.19                                                                               R.sub.f *                                                                             Starting compound                             ______________________________________                                         LVI    (R&S) iPr  CH.sub.3                                                                               0.78 (I)                                                                              XLIII                                         LVII   (R&S) iBu  tBu     0.86 (I)                                                                              IL                                            LVIII  (R&S) cPent                                                                               CH.sub.3                                                                               0.63 (C)                                                                              L                                             LIX    (R&S) cHex CH.sub.3                                                                               0.74 (I)                                                                              LI                                            LX     (R&S) cHex tBu     0.58 (C)                                                                              LII                                           LXI    (R&S) cHept                                                                               CH.sub.3                                                                               0.59 (P)                                                                              LIII                                          LXII   (R&S) cHept                                                                               tBu     0.84 (I)                                                                              LIV                                           LXIII  (R&S) Ph   CH.sub.3                                                                               0.74 (I)                                                                              XLVI                                          ______________________________________                                    

PREPARATION EXAMPLES Example 1

tert-Butyl 2-(R&S)-cyclopentyl-2- 4-(1,3-dimethyl-2,6-dioxo-8-(4-methyl)phenyl-1,2,3,6-tetrahydro-purin-7-ylmethyl)phenyl!acetate ##STR59##

5.4 g (25 mmol) of the compound from Example I were suspended in DMF (100 ml) at 22° C. and treated with 0.8 g (60% in paraffin, 22 mmol) of NaH. After 30 min at 40° C., the solution was treated with the compound from Example LV. The mixture was stirred at room temperature for a further 16 h. Water was added and the precipitate obtained was filtered off with suction. The moderately moist solid was stirred with dichloromethane and filtered off with suction.

Yield 9.3 g (88%);

R_(f) =0.48 (dichloromethane:methanol, 20:1);

Mass (calculated) for C₃₂ H₃₈ N₄ O₄ =542.68, mass spectrum (CI (NH₃), rel. intensity) 560 (25%, M+NH₄), 543 (100%);

¹ H NMR (300 MHz, CDCl₃) δ7.42 (d, 2 H), 7.28-7.20 (m, 4 H), 6.95 (d, 2 H), 5.60 (s, 2 H), 3.61 (s, 3 H), 3.40 (s, 3 H), 3.10 (d, 1 H), 2.42 (m, 1 H), 2.40 (s, 3 H), 1.90 (m, 1 H), 1.70-1.20 (m, 6 H), 1.41 (s, 9 H), 0.95 (m, 1 H).

The compounds shown in Tables 1, 2 and 3 are prepared in analogy to the procedure of Example

                                      TABLE 1                                      __________________________________________________________________________      ##STR60##                                                                                                   M.p.       Yield  Starting                       Ex. No.                                                                            R.sup.1                                                                              R.sup.5     R.sup.20                                                                          R.sub.f *                                                                           (°C.)                                                                       Mass spectrum                                                                         (% of theory)                                                                         compound                       __________________________________________________________________________      2  (R&S)cPent                                                                           H           tBu                                                                               0.54 (K)                                                                            134 453(100%)                                                                             65                                     3  (R&S)cPent                                                                           Br          tBu                                                                               0.40 (J)                                                                            162 531(25%)                                                                              74                                                                      57(100%)                                      4  (R&S)cPent                                                                           CH.sub.3    tBu                                                                               0.23 (J)                                                                            162 467(100%)                                                                             68     IV                              5  (R&S)cPent                                                                           Et          tBu                                                                               0.22 (J)                                                                            145 481(40%)                                                                              50     V                                                                57(100%)                                      6  (R&S)cPent                                                                           cPr         tBu                                                                               0.23 (J)                                                                            74  493(100%)                                                                             70     VI                              7  (R&S)cPent                                                                           cPent       tBu                                                                               0.30 (J)                                                                            63  521(20%)                                                                              68                                                                  (Foam)                                                                             57(100%)                                      8  (R&S)cPent                                                                           CH.sub.2 cHex                                                                              tBu                                                                               0.38 (J)                                                                            112 549(80%)                                                                              71     VII                                                              57(100%)                                      9  (R&S)cPent                                                                            ##STR61##  CH.sub.3                                                                          0.41 (J)                                                                            148 508(100%)                                                                             66                                    10  (R&S)cPent                                                                            ##STR62##  tBu                                                                               0.11 (T)        84     VIII                           11  (R&S)cPent                                                                            ##STR63##  tBu                                                                               0.31 (J)                                                                            105 543(60%) 57(100%)                                                                     60     IX                             12  (R&S)cPent                                                                            ##STR64##  tBu                                                                               0.37 (J)                                                                            98  543(100%)                                                                             64     X                              13  (R&S)cPent                                                                            ##STR65##  tBu                                                                               0.39 (J)                                                                            88 (Foam)                                                                          557(100%)                                                                             66     XI                             14  (R&S)cPent                                                                            ##STR66##  CH.sub.3                                                                          0.46 (J)                                                                            104 (Foam)                                                                         563(100%)                                                                             52     XII                            15  (R&S)cPent                                                                            ##STR67##  tBu                                                                               0.24 (J)                                                                            90 (Foam)                                                                          563(80%) 57(100%)                                                                     40     XIII                           16  (R&S)cPent                                                                            ##STR68##  tBu                                                                               0.26 (J)                                                                            --  597(80%) 57(100%)                                                                     53     XIV                            17  (R&S)cPent                                                                            ##STR69##  tBu                                                                               0.36 (J)                                                                            96 (Foam)                                                                          *559(100%)                                                                            51     XV                             18  (R&S)cPent                                                                            ##STR70##  tBu                                                                               0.06 (J)                                                                            (Foam)                                                                             571(80%) 298(100%)                                                                    36     XVI                            19  (R&S)cPent                                                                            ##STR71##  tBu                                                                               0.3 (J)                                                                             84 (Foam)                                                                          600(100%) 599(100%)                                                                   61     XVII                           20  (R&S)cPent                                                                            ##STR72##  tBu                                                                               0.41 (J)                                                                            155 529(40%) 473(100%)                                                                    57     XVIII                          21  (R&S)cPent                                                                            ##STR73##  tBu                                                                               0.25 (J)                                                                            --  530(50%) 57(100%)                                                                     20     XIX                            22  (R&S)cPent                                                                            ##STR74##  tBu                                                                               0.15 (K)                                                                            >240                                                                               530(100%)                                                                             52     XX                             23  (R&S)cPent                                                                            ##STR75##  tBu                                                                               0.41 (J)                                                                            173 535(40%) 57(100%)                                                                     68     XXI                            24  (R&S)cPent                                                                            ##STR76##  tBu                                                                               0.26 (E)                                                                            --  535(100%) 534(80%)                                                                    60     XXII                           25  (R&S)cPent                                                                            ##STR77##  tBu                                                                               0.52 (J)                                                                            193 549(70%) 57(100%)                                                                     66     XXIII                          26  (R&S)cPent                                                                            ##STR78##  tBu                                                                               0.45 (J)                                                                            78 (Foam)                                                                          549(50%) 57(100%)                                                                     53     XXIV                           27  (R&S)cPent                                                                            ##STR79##  tBu                                                                               0.44 (J)                                                                            165 615(60%) 57(100%)                                                                     54     XXV                            28  (R&S)cPent                                                                            ##STR80##  tBu                                                                               0.79 (G)                                                                            207 555(75%) 57(100%)                                                                     59     XXVI                           __________________________________________________________________________

                                      TABLE 2                                      __________________________________________________________________________      ##STR81##                                                                                                    M.p.       Yield  Starting                      Ex. No.                                                                            R.sup.1                                                                              R.sup.21    R.sup.22                                                                           R.sub.f *                                                                           (°C.)                                                                       Mass spectrum                                                                         (% of theory)                                                                         compound                      __________________________________________________________________________     29  (R&S)cPent                                                                           tBu         H   0.26 (J)                                                                            136 543(60%)                                                                              68                                                                      57(100%)                                    30  (R&S)cHex                                                                            CH.sub.3    H   0.21 (J)                                                                            131 515(100%)                                                                             80                                   31  (R&S)cHept                                                                           tBu         H   0.76 (K)                                                                            82  571(100%)                                                                             86                                   32  (R&S) CH.sub.3    H   0.23 (J)                                                                            92  509(100%)                                                                             44                                       Phenyl                                                                     33  (R&S)cPent                                                                           tBu         2-CH.sub.3                                                                         0.29 (J)                                                                            148 557(100%)                                                                             55     XXVII                         34  (R&S)cPent                                                                           tBu         3-CH.sub.3                                                                         0.40 (J)                                                                            65  557(60%)                                                                              51     XXVIII                                                       (Foam)                                                                             57(100%)                                    35  (R&S)cPent                                                                           tBu         4-CH.sub.3                                                                         0.17 (J)                                                                            165 557(100%)                                                                             56     XXIX                          36  (R&S)cPent                                                                           tBu         4-  0.35 (J)                                                                            90  619(60%)                                                                              58     XXX                                                 Phenyl   (Foam)                                                                             57(100%)                                    37  (R&S)cPent                                                                           tBu         2-Cl                                                                               0.26 (J)                                                                            156 577(40%)                                                                              61     XXXI                                                             57(100%)                                    38  (R&S)cPent                                                                           tBu         3-Cl                                                                               0.21 (J)                                                                            135 577(100%                                                                              40     II                            39  (R&S)cPent                                                                           tBu         4-F 0.17 (J)                                                                            162 561(100%)                                                                             60     XXXII                                                            505(100%)                                   40  (R&S)cPent                                                                           tBu         2-OCH.sub.3                                                                        0.21 (J)                                                                            138 573(40%)                                                                              64     XXXIII                                                           57(100%)                                    41  (R&S)cPent                                                                           tBu         3-OCH.sub.3                                                                        0.19 (J)                                                                            --  573(60%)                                                                              72     XXXIV                                                            57(100%)                                    42  (R&S)cPent                                                                           tBu         4-OCH.sub.3                                                                        0.28 (J)                                                                            75  573(80%)                                                                              48     XXXV                                                         (Foam)                                                                             57(100%)                                    __________________________________________________________________________

                                      TABLE 3                                      __________________________________________________________________________      ##STR82##                                                                                                             M.p.                                                                               Mass   Yield  Starting             Ex. No.                                                                            R.sup.1                                                                            R.sup.3                                                                            R.sup.4                                                                            R.sup.5   R.sup.23                                                                           T  V  R.sub.f *                                                                          (°C.)                                                                       spectrum                                                                              (% of                                                                                 compound             __________________________________________________________________________     43  (R&S)                                                                              C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    H         tBu O  O  0.28                                                                               01  481(100%)                                                                             76     III                      cPent                           (J)     57(90%)                            44  (R&S)                                                                              C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    CH.sub.3  tBu O  O  0.22                                                                               167 495(50%)                                                                              66     XXXVII                   cPent                           (J)     57(100%)                           45  (R&S)                                                                              C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          tBu O  O  0.34                                                                               121-24                                                                             509(100%)                                                                             69     XXXVIII                  cPent                           (J)     57(80%)                            46  (R&S)                                                                              C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    cPro      CH.sub.3                                                                           O  O  0.40                                                                               128 479(80%)                                                                              49     XXIX                     cPent                           (J)     55(100%)                           47  (R&S)                                                                              C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    Phenyl    CH.sub.3                                                                           O  O  0.26                                                                               58  515(100%)                                                                             57                              cPent                           (J) (Foam)                                 48  (R&S) cPent                                                                        C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                     ##STR83##                                                                               CH.sub.3                                                                           O  O  0.40 (J)                                                                           58 (Foam)                                                                          529(100%)                                                                             46     XL                   49  (R&S) cPent                                                                        C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                     ##STR84##                                                                               CH.sub.3                                                                           O  O  0.58 (J)                                                                           166 521(85%) 55(100%)                                                                     65     XLI                  50  (R&S)                                                                              CH.sub.3                                                                           tBu H         tBu O  O  0.64                                                                               --  495(60%)                                                                              69                              cPent                           (J)     57(100%)                           51  (R&S)                                                                              CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3  tBu S  O  0.43                                                                               158-60                                                                             483(60%)                                                                              68     XLII                     cPent                           (J)     427(100%)                                                                      57(100%)                           52  (R&S)                                                                              CH.sub.3                                                                           CH.sub.3                                                                           C.sub.2 H.sub.5                                                                          tBu S  O  0.60                                                                               178-82                                                                             497(80%)                                                                              68     XLIII                    cPent                           (J)     441(100%)                                                                      57(100%)                           53  (R&S) cPent                                                                        CH.sub.3                                                                           CH.sub.3                                                                            ##STR85##                                                                               tBu S  O  0.84 (J)                                                                           180-83                                                                             551(20%) 57(100%)                                                                     57     XLIV                 54  (R&S) cPent                                                                        CH.sub.3                                                                           CH.sub.3                                                                            ##STR86##                                                                               tBu S  O  0.88                                                                               158-62                                                                             559(20%) 57(100%)                                                                     68     XLV                  __________________________________________________________________________

Example 55

2-(R&S)-Cyclopentyl-2- 4-(1,3-dimethyl-2,6-dioxo-8-(3-hydroxy-phenyl)-methyl-1,2,3,6-tetrahydro-purin-7-yl-methyl)phenyl!acetate ##STR87##

5.26 g (9.18 mmol) of the compound from Example 41 are dissolved in 50 ml of CH₂ Cl₂ and the solution is cooled to -78° C. 45.9 ml (45.9 mmol; 1 molar in CH₂ Cl₂) of boron tribromide are slowly added to this. The mixture is subsequently stirred at room temperature for 2 hours. It is then cooled again to 0° C. with an ice bath and treated with 50 ml of methanol. It is subsequently stirred overnight at room temperature. The solvent is evaporated using a rotary evaporator, and the residue is taken up in CH₂ Cl₂ and water and extracted. The organic phase is dried over sodium sulphate, in the course of which crystals precipitate out, which go into solution again with addition of a little methanol. The sodium sulphate is filtered off with suction and the mother liquor is concentrated in a rotary evaporator. The residue (crystals) is stirred in CH₂ Cl₂ and filtered off with suction.

Yield (36%)

R_(f) =0.27 (dichloromethane:methanol, 20:1)

M.p.=160° C.

In analogy to the procedure of Example 55, the compounds shown in Table 4 are prepared:

                                      TABLE 4                                      __________________________________________________________________________      ##STR88##                                                                                                  Yield                                             Ex.              M.p. Mass   (% of                                                                              Starting                                      No.                                                                               R.sup.1                                                                             R.sup.24                                                                          R.sub.f *                                                                            (°C.)                                                                        spectrum                                                                              theory)                                                                            compound                                      __________________________________________________________________________     56 (R&S)                                                                               2-OH                                                                              0.31 (K)                                                                             (Foam)                                                                              503(100%)                                                                             29  40                                               cPent                                                                       57 (R&S)                                                                               4-OH                                                                              0.16 (K)                                                                             100  503(100%)                                                                             73  42                                               cPent         (Foam)                                                        __________________________________________________________________________

Example 58

2-(R&S)-Cyclopentyl- 4-(1,3-dimethyl-2,6-dioxo-8-(4-methyl)phenyl-1,2,3,6-tetrahydro-purin-7-ylmethyl)phenyl!acetic acid hydrochloride ##STR89##

8.3 g (15.3 mmol) of the compound from Example 1 were dissolved in dioxane (60 ml), treated with concentrated hydrochloric acid and heated under reflux for 4 h. The mixture was cooled and treated with cold water. It was subsequently stirred for 20 minutes, and the crystals obtained were filtered off with suction.

Yield 7.21 g (97%);

M.p.>240° C.;

Rf=0.23 (dichloromethane:methanol, 20:1);

Mass (calculated for C₂₈ H₃₀ N₄ O₄ =486.58, mass spectrum (FAB, rel. intensity) 487 (100%);

¹ H NMR (300 MHz, CDCl₃) δ7.45 (d, J=8.19 Hz, 2 H), 7.28-7.23 (m, 4 H), 6.98 (d, J=8.18 Hz, 2 H), 5.60 (s, 2 H), 3.64 (s, 3 H), 3.40 (s, 3 H), 3.23 (d, J=11.08 Hz, 1 H), 2.41 (m, 1 H), 2.40 (s, 3 H), 1.92 (m, 1 H), 1.70-1.20 (m, 6 H), 0.97 (m, 1 H).

The compounds shown in Tables 5, 6 and 7 are prepared in analogy to the procedure of Example

                                      TABLE 5                                      __________________________________________________________________________      ##STR90##                                                                                                       Yield                                        Ex.                     M.p.                                                                               Mass  (% of                                                                              Starting                                 No.                                                                               R.sup.1                                                                            R.sup.24    R.sub.f *                                                                           (°C.)                                                                       spectrum                                                                             theory)                                                                            compound                                 __________________________________________________________________________     59 (R&S)                                                                              H           0.27 (K)                                                                            94  *397(40%)                                                                            76   2                                          cPent                (Foam)                                                 60 (R&S)                                                                              Br          0.35 (K)                                                                            192       82   3                                          cPent                                                                       61 (R&S)                                                                              CH.sub.3    0.22 (K)                                                                            >230                                                                               411(100%)                                                                            100  4                                          cPent                                                                       62 (R&S)                                                                              C.sub.2 H.sub.5                                                                            0.20 (K)                                                                            197 425(100%)                                                                            64   5                                          cPent                                                                       63 (R&S)                                                                              cPro        0.29 (K)                                                                            94  437(100%)                                                                            100  6                                          cPent                                                                       64 (R&S)                                                                              cPent       0.47 (K)                                                                            96  465(100%)                                                                            83   7                                          cPent                (Foam)                                                 65 (R&S)                                                                              CH.sub.2 -  0.38 (K)                                                                            217 *493(100%)                                                                           74   8                                          cPent                                                                              cHex                                                                    66 (R&S) cPent                                                                         ##STR91##  0.31 (K)                                                                            190 493(100%)                                                                            41   9                                       67 (R&S) cPent                                                                         ##STR92##  0.39 (J)       100 10                                       68 (R&S) cPent                                                                         ##STR93##  0.28 (K)                                                                            185 487(100%)                                                                            100 11                                       69 (R&S) cPent                                                                         ##STR94##  0.24 (K)                                                                            155 487(100%)                                                                            84  12                                       70 (R&S) cPent                                                                         ##STR95##  0.35 (K)                                                                            165 501(100%)                                                                            96  13                                       71 (R&S) cPent                                                                         ##STR96##  0.36 (K)                                                                            218 549(100%)                                                                            56  14                                       72 (R&S) cPent                                                                         ##STR97##  0.33 (K)                                                                            130 (Foam)                                                                         507(100%)                                                                            67  15                                       73 (R&S) cPent                                                                         ##STR98##  0.31 (K)                                                                            132 541(80%) 149(100%)                                                                   85  16                                       74 (R&S) cPent                                                                         ##STR99##  0.35 (K)                                                                            122 (Foam)                                                                         503(100%)                                                                            88  17                                       75 (R&S) cPent                                                                         ##STR100## 0.29 (K)                                                                            >245                                                                               *516(70%) 307(100%)                                                                  88  18                                       76 (R&S) cPent                                                                         ##STR101## 0.46 (K)                                                                            (Foam)                                                                             544(100%)                                                                            100 19                                       77 (R&S) cPent                                                                         ##STR102## 0.23 (K)                                                                            >240                                                                               474(100%)                                                                            83  20                                       78 (R&S) cPent                                                                         ##STR103## 0.52 (L)                                                                            --  474(100%)                                                                            27  21                                       79 (R&S) cPent                                                                         ##STR104## 0.25 (L)                                                                            >240                                                                               474(100%)                                                                            72  22                                       80 (R&S) cPent                                                                         ##STR105## 0.23 (K)                                                                            217 479(100%)                                                                            66  23                                       81 (R&S) cPent                                                                         ##STR106## 0.34 (K)                                                                            215-16                                                                             479(100%)                                                                            45  24                                       82 (R&S) cPent                                                                         ##STR107## 0.32 (K)                                                                            >235                                                                               493(100%)                                                                            100 25                                       83 (R&S) cPent                                                                         ##STR108## 0.23 (K)                                                                            112 (Foam)                                                                         493(100%)                                                                            81  26                                       84 (R&S) cPent                                                                         ##STR109## 0.35 (K)                                                                            >235                                                                               557(100%)                                                                            100 27                                       85 (R&S) cPent                                                                         ##STR110## 0.35 (K)                                                                            >240                                                                               476(50%)  28                                       __________________________________________________________________________

                                      TABLE 6                                      __________________________________________________________________________      ##STR111##                                                                                                 Yield                                             Ex.              M.p. Mass   (% of                                                                              Starting                                      No.                                                                               R.sup.1                                                                             R.sup.25                                                                           R.sub.f *                                                                           (°C.)                                                                        spectrum                                                                              theory)                                                                            compound                                      __________________________________________________________________________     86 (R&S)                                                                               H   0.44 (K)                                                                            97   487(100%)                                                                             90  29                                               cPent                                                                       87 (R&S)                                                                               H   0.29 (K)                                                                            117  501(100%)                                                                             55  30                                               cHex          (Foam)                                                        88 (R&S)                                                                               H   0.41 (K)                                                                            214  *514(100%)                                                                            60  31                                               cHept                                                                       89 (R&S)Ph                                                                             H   0.22 (K)                                                                            130  495(100%)                                                                             42  32                                            90 (R&S)                                                                               2-CH.sub.3                                                                         0.42 (K)                                                                            192  501(100%)                                                                             94  33                                               cPent                                                                       91 (R&S)                                                                               3-CH.sub.3                                                                         0.24 (K)                                                                            196  501(100%)                                                                             91  34                                               cPent                                                                       92 (R&S)                                                                               4-CH.sub.3                                                                         0.27 (K)                                                                            222  501(100%)                                                                             97  35                                               cPent                                                                       93 (R&S)                                                                               4-Ph                                                                               0.13 (K)                                                                            215  563(100%)                                                                             100 36                                               cPent                                                                       94 (R&S)                                                                               2-Cl                                                                               0.34 (K)                                                                            155  521(100%)                                                                             100 37                                               cPent                                                                       95 (R&S)                                                                               3-Cl                                                                               0.25 (K)                                                                            194  521(100%)                                                                             68  38                                               cPent                                                                       96 (R&S)                                                                               4-F 0.25 (K)                                                                            213  505(100%)                                                                             94  39                                               cPent                                                                       97 (R&S)                                                                               2-OCH.sub.3                                                                        0.28 (K)                                                                            63   517(100%)                                                                             100 40                                               cPent                                                                       98 (R&S)                                                                               3-OCH.sub.3                                                                        0.22 (K)                                                                            188  517(100%)                                                                             64  41                                               cPent                                                                       99 (R&S)                                                                               4-OCH.sub.3                                                                        0.26 (K)                                                                            210  517(100%)                                                                             92  42                                               cPent                                                                       __________________________________________________________________________

                                      TABLE 7                                      __________________________________________________________________________      ##STR112##                                                                                                     M.p.                                                                               Mass   Yield  Starting                    Ex. No.                                                                            R.sup.1                                                                            R.sup.3                                                                           R.sup.4                                                                           R.sup.5   T V R.sub.f *                                                                           (°C.)                                                                       spectrum                                                                              (% of theory)                                                                         compound                    __________________________________________________________________________     100 (R&S)                                                                              C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H         O O 0.27 (K)                                                                            110 425 (100%)                                                                            100    43                              cPent                                                                      101 (R&S)                                                                              C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   CH.sub.3  O O 0.24 (K)                                                                            82-85                                                                              439 (100%)                                                                            100    44                              cPent                                                                      102 (R&S)                                                                              C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                          O O 0.20 (K)                                                                            181 453 (100%)                                                                            96     45                              cPent                                                                      103 (R&S)                                                                              C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   cPro      O O 0.30 (K)                                                                            98  465 (100%)                                                                            78     46                              cPent                        (Foam)                                        104 (R&S)                                                                              C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   Ph        O O 0.38 (K)                                                                            100 501 (100%)                                                                            80     47                              cPent                        (Foam)                                        105 (R&S) cPent                                                                        C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    ##STR113##                                                                              O O 0.16 (K)                                                                            92 (Foam)                                                                          515 (100%)                                                                            75     48                          106 (R&S) cPent                                                                        C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    ##STR114##                                                                              O O 0.33 (K)                                                                            232 507 (80%) 464 (100%)                                                                  85     49                          107 (R&S)                                                                              CH.sub.3                                                                          iBu                                                                               H         O O 0.33 (K)                                                                            76  439 (100%)                                                                            98     50                              cPent                        (Foam)                                        108 (R&S)                                                                              CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3  S O 0.12 (J)                                                                            222 427 (100%)                                                                            100    51                              cPent                                                                      109 (R&S)                                                                              CH.sub.3                                                                          CH.sub.3                                                                          C.sub.2 H.sub.5                                                                          S O 0.14 (J)                                                                            172 441 (100%)                                                                            100    52                              cPent                                                                      110 (R&S) cPent                                                                        CH.sub.3                                                                          CH.sub.3                                                                           ##STR115##                                                                              S O 0.15 (J)                                                                            >235                                                                               495 (100%)                                                                            100    53                          111 (R&S) cPent                                                                        CH.sub.3                                                                          CH.sub.3                                                                           ##STR116##                                                                              S O 0.26 (J)                                                                            >235                                                                               503 (40%) 55 (100%)                                                                   86     54                          __________________________________________________________________________

Example 112

N- 2-(R)-Phenyl-1-hydroxyethane!-2-(R&S)-cyclopentyl- 4-(1,3-dimethyl)-2,6-dioxo-8-(4-methyl)phenyl-1,2,3,6-tetrahydro-purin-7-ylmethyl)phenyl!acetamide ##STR117##

6.1 g (12.5 mmol) of the compound from Example 58, (R)-phenylglycinol (1.71 g, 12.5 mmol), 1-hydroxy-1-benzotriazole (1.86 g, 13.8 mmol), N'-(3-dimethylamino-propyl)-N-ethylcarbodiimide hydrochloride(2.76 g, 14.4 mmol) and triethylamine (2.53 g, 25 mmol) are dissolved successively in CH₂ Cl₂ and stirred overnight at room temperature. A further 15 ml of CH₂ Cl₂ are added and the mixture is washed with aqueous NH₄ Cl and NaHCO₃ solution and with water. The organic phase is dried over sodium sulphate and evaporated. The residue is purified by column chromatography.

Yield 6.59 g (87%);

M.p. 87° C. (foam);

R_(f) =0.32 (dichloromethane:methanol, 20:1);

Mass (calculated) for C₃₆ H₃₉ N₅ O₄ =605.75, mass spectrum (FAB, rel. intensity) 606 (100%), 105 (95%).

The compounds shown in Tables 8, 9 and 10 are prepared in analogy to the procedure of Example 112. The compounds are either obtained directly as pure diastereomers, or they are separated by column chromatography according to customary methods starting from the racemate.

                                      TABLE 8                                      __________________________________________________________________________      ##STR118##                                                                                               M.p.         Yield  Starting                        Ex. No.                                                                            R.sup.1                                                                              R.sup.5     R.sub.f *                                                                           (°C.)                                                                         Mass spectrum                                                                         (% of theory)                                                                         compound                        __________________________________________________________________________     113 (R&S) cPent                                                                          H           0.27 (K)                                                                            96 (Foam)                                                                            516 (100%)                                                                            70     59                              114 (dia A) cPent                                                                        H           0.27 (K)                                                                            (Foam)              113                             115 (dia B) cPent                                                                        H           0.25 (K)                                                                            162-163             113                             116 (R&S) cPent                                                                          Br          0.33 (K)                                                                            109 (Foam)                                                                           596 (35%)                                                                             88     60                                                               171 (100%)                                    117 (dia A) cPent                                                                        Br               183-185                                                                              596 (35%)     116                                                              572 (100%)                                    118 (dia B) cPent                                                                        Br               118-23                                                                               596 (35%)     116                                                              550 (100%)                                    119 (R&S) cPent                                                                          CH.sub.3    0.35 (K)                                                                            126-28                                                                               530 (60%)                                                                             85     61                                                               105 (100%)                                    120 (R&S) cPent                                                                          C.sub.2 H.sub.5                                                                            0.27 (K)                                                                            105   544 (100%)                                                                            72     62                                                         (Foam)                                              121 (R&S) cPent                                                                          cPro        0.36 (K)                                                                            110   556 (80%)                                                                             73     63                                                         (Foam)                                                                               105 (100%)                                    122 (R&S) cPent                                                                          cPent       0.33 (K)                                                                            194   584 (100%)                                                                            65     64                              123 (R&S) cPent                                                                          CH.sub.2 cHex                                                                              0.31 (K)                                                                            117   612 (100%)                                                                            69     65                                                         (Foam)                                              124 (dia A) cPent                                                                        CH.sub.2 cHex                                                                              0.46 (K)                                                                            173   C, HN Pent    123                             125 (dia B) cPent                                                                        CH.sub.2 cHex                                                                              0.46 (K)                                                                            90 (Foam)                                                                            612 (100%)    123                             126 (R&S) cPent                                                                           ##STR119## 0.35 (K)                                                                            112 (Foam)                                                                           612 (100%)                                                                            81     66                              127 (dia A) cPent                                                                         ##STR120## 0.16 (K)                                                                            183   612 (50%) 227 (100%)                                                                         126                             128 (dia B) cPent                                                                         ##STR121## 0.16 (K)                                                                            82 (Foam)                                                                            612 (40%) 105 (100%)                                                                         126                             129 (R&S) cPent                                                                           ##STR122## 0.50 (L)          98     67                              130 (dia A) cPent                                                                         ##STR123## 0.50 (L)   592 (100%)    129                             131 (dia B) cPent                                                                         ##STR124## 0.50 (L)   592 (100%)    129                             132 (R&S) cPent                                                                           ##STR125## 0.31 (K)                                                                            128 (Foam)                                                                           606 (100%)                                                                            79     68                              133 (R&S) cPent                                                                           ##STR126## 0.25 (K)                                                                            115 (Foam)                                                                           606 (100%)                                                                            81     69                              134 (dia A) cPent                                                                         ##STR127## 0.23 (K)                                                                            189-91                                                                               606 (50%) 171 (100%)                                                                         133                             135 (dia B) cPent                                                                         ##STR128## 0.25 (K)                                                                            154   606 (100%)    133                             136 (dia A) cPent                                                                         ##STR129## 0.46 (K)                                                                            104 (Foam)          112                             137 (dia B) cPent                                                                         ##STR130## 0.46 (K)                                                                            198 (Foam)          112                             138 (R&S) cPent                                                                           ##STR131## 0.25 (K)                                                                            132 (Foam)                                                                           620 (100%)                                                                            85     70                              139 (R&S) cPent                                                                           ##STR132## 0.28 (K)                                                                            105 (Foam)                                                                           668 (70%) 154 (100%)                                                                  86     71                              140 (R&S) cPent                                                                           ##STR133## 0.34 (K)                                                                            132 (Foam)                                                                           626 (100%)                                                                            85     72                              141 (dia A) cPent                                                                         ##STR134## 0.45 (K)                                                                            80 (Foam)           140                             142 (dia B) cPent                                                                         ##STR135## 0.45 (K)                                                                            198                 140                             143 (R&S) cPent                                                                           ##STR136## 0.34 (K)                                                                            130 (Foam)                                                                           660 (100%)                                                                            69     73                              144 (dia A) cPent                                                                         ##STR137## 0.47 (K)                                                                            245   660 (50%) 171 (100%)                                                                         143                             145 (dia B) cPent                                                                         ##STR138## 0.45 (K)                                                                            212   C, H, N Anal. 143                             146 (R&S) cPent                                                                           ##STR139## 0.20 (K)                                                                            126 (Foam)                                                                           622 (100%)                                                                            84     74                              147 (dia A) cPent                                                                         ##STR140## 0.43 (K)                                                                            O1    622 (351) 105 (100%)                                                                         146                             148 (dia B) cPent                                                                         ##STR141## 0.45 (K)                                                                            201   C, H, N Anal. 146                             149 (R&S) cPent                                                                           ##STR142## 0.25 (K)                                                                            140 (Foam)                                                                           635 (100%)                                                                            13     75                              150 (R&S) cPent                                                                           ##STR143## 0.24 (K)                                                                            128 (Foam)                                                                           663 (100%)                                                                            72     76                              151 (R&S) cPent                                                                           ##STR144## 0.28 (K)                                                                            >240  593 (100%)                                                                            64     77                              152 (R&S) cPent                                                                           ##STR145## 0.14 (K)                                                                            123 (Foam)                                                                           593 (100%)                                                                            81     78                              153 (R&S) cPent                                                                           ##STR146##                          79                              154 (R&S) cPent                                                                           ##STR147## 0.21 (K)                                                                            115 (Foam)                                                                           598 (60%) 105 (100%)                                                                  82     80                              155 (dia A) cPent                                                                         ##STR148## 0.43 (K)                                                                            174-76                                                                               598 (100%)    154                             156 (dia B) cPent                                                                         ##STR149## 0.49 (K)                                                                            197-99                                                                               598 (100%)    154                             157 (R&S) cPent                                                                           ##STR150## 0.30 (K)                                                                            (Foam)                                                                               598(30%) 307 (100%)                                                                   49     81                              158 (dia A) cPent                                                                         ##STR151## 0.34 (K)                                                                            136                 157                             159 (dia B) cPent                                                                         ##STR152## 0.31 (K)                                                                            128                 157                             160 (R&S) cPent                                                                           ##STR153## 0.46 (K)                                                                            155   612 (100%)                                                                            60     82                              161 (dia A) cPent                                                                         ##STR154## 0.41 (K)                                                                            123   612 (100%)    160                             162 (dia B) cPent                                                                         ##STR155## 0.37 (K)                                                                            187   C, H, N Anal. 160                             163 (R&S) cPent                                                                           ##STR156## 0.39 (J)                                                                            97 (Foam)                                                                            612 (60%) 57 (100%)                                                                   85     83                              164 (R&S) cPent                                                                           ##STR157## 0.48 (K)                                                                            >235  676(20%) 55 (100%)                                                                    61     84                              165 (dia A) cPent                                                                         ##STR158## 0.37 (K)                                                                            175   C, H, N Anal. 164                             166 (dia B) cPent                                                                         ##STR159## 0.37 (K)                                                                            169   676 (100%)    164                             167 (R&S) cPent                                                                           ##STR160## 0.49 (K)                                                                            160-69                                                                               618 (100%)                                                                            31     85                              __________________________________________________________________________

                                      TABLE 9                                      __________________________________________________________________________      ##STR161##                                                                                        M.p.       Yield  Starting                                 Ex. No.                                                                            R.sup.1                                                                              R.sup.26                                                                            R.sub.f *                                                                           (°C.)                                                                       Mass spectrum                                                                         (% of theory)                                                                         compound                                 __________________________________________________________________________     168 (R&S)cPent                                                                           H    0.22 (K)                                                                            (Foam)                                                                             606(100%)                                                                             98     86                                       169 (dia A)cPent                                                                         H         204-7             168                                      170 (dia B)cPent                                                                         H         (Foam)            168                                      171 (R&S)cHex                                                                            H    0.40 (K) 620(100%)                                                                             86     87                                       172 (dia A)cHex                                                                          H    0.33 (K)                                                                            226 C, H, N Anal. 171                                      173 (dia B)cHex                                                                          H    0.34 (K)                                                                            116 620(45%)      171                                                              185(100%)                                              174 (R&S)cHept                                                                           H    0.36 (K)                                                                            108        92     88                                                           (Foam)                                                     175 (dia A)cHept                                                                         H         202               174                                      176 (dia B)cHept                                                                         H         100               174                                                          (Foam)                                                     177 (R&S)Ph                                                                              H    0.15 (K)                                                                            106-10                                                                             614(100%)                                                                              50%   89                                       178 (R&S)cPent                                                                           2-CH.sub.3                                                                          0.38 (K)                                                                            137 620(100%)                                                                             54     90                                       179 (R&S)cPent                                                                           3-CH.sub.3                                                                          0.28 (K)                                                                            121 620(100%)                                                                             36     91                                                           (Foam)                                                     180 (dia A)cPent                                                                         3-CH.sub.3                                                                          0.16 (K)                                                                            200 C, H, N Anal. 179                                      181 (dia B)cPent                                                                         3-CH.sub.3                                                                          0.17 (K)                                                                            166               179                                      182 (R&S)cPent                                                                           4-CH.sub.3                                                                          0.33 (K)                                                                            113 620(100%)                                                                             92     92                                                           (Foam)                                                     183 (dia A)cPent                                                                         4-CH.sub.3                                                                          0.37 (K)                                                                            223 C, H, N Anal. 182                                      184 (dia B)cPent                                                                         4-CH.sub.3                                                                          0.40 (K)                                                                            208 C, H, N Anal. 182                                      185 (R&S)cPent                                                                           4-Phenyl                                                                            0.49 (K)                                                                            180 682(100%)                                                                             47     93                                       186 (dia A)cPent                                                                         4-Phenyl                                                                            0.32 (K)                                                                            >230                                                                               C, H, N Anal. 185                                      187 (dia B)cPent                                                                         4-Phenyl                                                                            0.31 (K)                                                                            200 C, H, N Anal. 185                                      188 (R&S)cPent                                                                           2-Cl 0.39 (K)                                                                            113 640(100%)                                                                             77     94                                                           (Foam)                                                     189 (dia A)cPent                                                                         2-Cl 0.38 (K)                                                                            208 C, H, N Anal. 188                                      190 (dia B)cPent                                                                         2-Cl 0.34 (K)                                                                            142 C, H, N Anal. 188                                      191 (R&S)cPent                                                                           3-Cl 0.41 (K)                                                                            142 640(100%)                                                                             86     95                                       192 (dia A)cPent                                                                         3-Cl 0.35 (K)                                                                            200 C, H, N Anal. 191                                      193 (dia B)cPent                                                                         3-Cl 0.35 (K)                                                                            183               191                                      194 (R&S)cPent                                                                           4-F  0.42 (K)                                                                            151 624(100%)                                                                             81     96                                                           (Foam)                                                     195 (dia A)cPent                                                                         4-F  0.38 (K)                                                                            212 C, H, N Anal. 194                                      196 (dia B)cPent                                                                         4-F  0.37 (K)                                                                            189 C, H, N Anal. 194                                      197 (R&S)cPent                                                                           2-OCH.sub.3                                                                         0.37 (K)                                                                            120 636(100%)                                                                             61     97                                                           (Foam)                                                     198 (R&S)cPent                                                                           3-OCH.sub.3                                                                         0.48 (K)                                                                            105 636(100%)                                                                             79     98                                                           (Foam)                                                     199 (dia A)cPent                                                                         3-OCH.sub.3                                                                         0.19 (K)                                                                            188               198                                      200 (dia B)cPent                                                                         3-OCH.sub.3                                                                         0.15 (K)                                                                            178               198                                      201 (R&S)cPent                                                                           4-OCH.sub.3                                                                         0.35 (K)                                                                            110 636(100%)                                                                             70     99                                                           (Foam)                                                     202 (dia A)cPent                                                                         4-OCH.sub.3                                                                         0.29 (K)               201                                      203 (dia B)cPent                                                                         4-OCH.sub.3                                                                         0.28 (K)               201                                      204 (R&S)cPent                                                                           2-OH 0.23 (K)                                                                            130 622(100%)                                                                             67     56                                       205 (dia A)cPent                                                                         2-OH 0.26 (K)                                                                            01  622(40%)      204                                                              105(100%)                                              206 (dia B)cPent                                                                         2-OH 0.26 (K)                                                                            01  622(50%)      204                                                              105(100%)                                              207 (R&S)cPent                                                                           3-OH 0.14 (K)                                                                            128 622(100%)                                                                             70     55                                                           (Foam)                                                     208 (dia A)cPent                                                                         3-OH 0.38 (K)                                                                            143 622(100%)     207                                      209 (dia B)cPent                                                                         3-OH 0.38 (K)                                                                            145 622(100%)     207                                      210 (R&S)cPent                                                                           4-OH                        57                                       __________________________________________________________________________

                                      TABLE 10                                     __________________________________________________________________________      ##STR162##                                                                    Ex.                                     M.p.                                                                               Mass   Yield  Starting             No.                                                                               R.sup.1                                                                            R.sup.3                                                                           R.sup.4                                                                            R.sup.5   R.sup.14                                                                           R.sup.15                                                                           T  V R.sub.f *                                                                         (°C.)                                                                       spectrum                                                                              (% of                                                                                 compound             __________________________________________________________________________     211                                                                               (R&S)                                                                              C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    H         (R)Ph                                                                              CH.sub.2 OH                                                                        O  O 0.40   544(100%)                                                                             67     100                     cPent                             (J)                                       212                                                                               (dia A)                                                                            C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    H         (R)Ph                                                                              CH.sub.2 OH                                                                        O  O 0.40                                                                              110               211                     cPent                             (J)                                       213                                                                               (dia B)                                                                            C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    H         (R)Ph                                                                              CH.sub.2 OH                                                                        O  O 0.35                                                                              121               211                     cPent                             (J)                                       214                                                                               (R&S)                                                                              C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    CH.sub.3  (R)Ph                                                                              CH.sub.2 OH                                                                        O  O 0.48                                                                              112-14                                                                             558(100%)                                                                             83     101                     cPent                             (K)                                       215                                                                               (R&S)                                                                              C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                          (R)Ph                                                                              CH.sub.2 OH                                                                        O  O 0.20                                                                              104 572(80%)                                                                              84     102                     cPent                             (J)                                       216                                                                               (R&S)                                                                              C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    cPro      (R)Ph                                                                              CH.sub.2 OH                                                                        O  O 0.36                                                                              104 584(100%)                                                                             87     103                     cPent                             (K)                                                                               (Foam)                                 217                                                                               (R&S)                                                                              C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    Ph        (R)Ph                                                                              CH.sub.2 OH                                                                        O  O 0.31                                                                              115 620(100%)                                                                             87     104                     cPent                             (K)                                                                               (Foam)                                 218                                                                               (R&S) cPent                                                                        C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                     ##STR163##                                                                              (R)Ph                                                                              CH.sub.2 OH                                                                        O  O 0.44 (K)                                                                          168 634(90%) 105(100%)                                                                    90     105                  219                                                                               (R&S) cPent                                                                        C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                     ##STR164##                                                                              (R)Ph                                                                              CH.sub.2 OH                                                                        O  O 0.38 (K)                                                                          115-17 (Foam)                                                                      626(70%) 105(100%)                                                                    90     106                  220                                                                               (R&S)                                                                              CH.sub.3                                                                          iBu H         (R)Ph                                                                              CH.sub.2 OH                                                                        O  O 0.39                                                                              101 558(100%)                                                                             79     107                     cPent                             (K)                                                                               (Foam)                                 221                                                                               (dia A)                                                                            CH.sub.3                                                                          iBu H         (R)Ph                                                                              CH.sub.2 OH                                                                        O  O 0.24                                                                              134 558(100%)     220                     cPent                             (K)                                       222                                                                               (dia B)                                                                            CH.sub.3                                                                          iBu H         (R)Ph                                                                              CH.sub.2 OH                                                                        O  O 0.20                                                                              186 C, H, N       220                     cPent                             (K)    Anal.                              223                                                                               (R&S)                                                                              CH.sub.3                                                                          CH.sub.3                                                                           CH.sub.3  (R)Ph                                                                              CH.sub.2 OH                                                                        S  O 0.45                                                                              120 546(90%)                                                                              68     108                     cPent                             (J)                                                                               (Foam)                                 224                                                                               (R&S)                                                                              CH.sub.3                                                                          CH.sub.3                                                                           C.sub.2 H.sub.5                                                                          (R)Ph                                                                              CH.sub.2 OH                                                                        S  O 0.45                                                                              113 560(100%)                                                                             58     109                     cPent                             (K)                                                                               (Foam)                                 225                                                                               (R&S) cPent                                                                        CH.sub.3                                                                          CH.sub.3                                                                            ##STR165##                                                                              (R)Ph                                                                              CH.sub.2 OH                                                                        S  O 0.64 (J)                                                                          130 (Foam)                                                                         614(90%) 154(100%)                                                                    46     110                  226                                                                               (R&S) cPent                                                                        CH.sub.3                                                                          CH.sub.3                                                                            ##STR166##                                                                              (R)Ph                                                                              CH.sub.2 OH                                                                        S  O 0.41 (J)                                                                          104 (Foam)                                                                         622(100%)                                                                             79     111                  __________________________________________________________________________

Example 227

2-(R&S)-Cyclopentyl-2- 4-(1,3-dimethyl-2,6-dioxo-8-(2-phenyl-ethyl)-1,2,3,6-tetra-hydro-purin-7-yl-methyl)phenyl!acet-N- 1-(R)-1-phenyl-2-hydroxy-ethyl)amide ##STR167##

0.40 g (0.648 mmol) of the compound from Example 167 is dissolved in 10 ml of methanol and 10 ml of acetic acid. A spatula tipful of palladium-carbon (10% strength) is added to this solution and it is hydrogenated for 4 hours under normal pressure. The mixture is filtered off with suction through Celite and concentrated in a rotary evaporator. The residue is taken up in CH₂ Cl₂ and water, adjusted to pH 8 with sodium hydrogen carbonate and extracted. The organic phase is dried over sodium sulphate and concentrated in a rotary evaporator. The residue is purified by column chromatography.

Yield: 0.180 g (44.9%)

R_(f) =0.16 (dichloromethane:methanol 20:1)

Mass (calculated) for C₃₇ H₄₁ N₅ O₄ =619.77 

We claim:
 1. Substituted xanthines of formula ##STR168## in which A represents a radical of the formula ##STR169## in which R³, R⁴, R⁶ and R⁷ are identical or different and denote hydrogen, cycloalkyl having 3 to 7 carbon atoms or aryl having 6 to 10 carbon atoms,or denote straight-chain or branched alkyl or alkenyl in each case having up to 8 carbon atoms, each of which is optionally substituted by halogen, hydroxyl or aryl having 6 to 10 carbon atoms, T, V, X and Y are identical or different and denote an oxygen or sulphur atom, R⁵ and R⁸ are identical or different and denote hydrogen, halogen, cycloalkyl having 3 to 8 carbon atoms or straight-chain or branched alkyl or alkenyl in each case having up to 8 carbon atoms, each of which is optionally substituted by 1) cycloalkyl having 3 to 8 carbon atoms, or by 2) a 5- to 6-membered, aromatic, optionally benzo-fused heterocycle having up to 3 heteroatoms from the series S, N and/or O, 3) or by aryl having 6 to 10 carbon atoms, where the cyclic substituents identified by 1), 2), and 3), can be substituted identically or differently up to 3 times by a 5- to 6-membered, aromatic heterocycle having up to 3 heteroatoms from the series S, N and/or O, or by phenyl, benzyl, halogen, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 6 carbon atoms, or R⁵ and R⁸ denote aryl having 6 to 10 carbon atoms or a 5- to 7-membered aromatic, optionally benzo-fused heterocycle having up to 3 heteroatoms from the series S, N and/or O, each of which is optionally substituted identically or differently up to 3 times by halogen, phenyl, trifluoromethyl, hydroxy, carboxyl or straight-chain of branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 6 carbon atoms or by a group of the formula --(CO)_(a) --NR⁹ R¹⁰, in whicha denotes a number 0 or 1, R⁹ and R¹⁰ are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl or acyl in each case having up to 5 carbon atoms, D and E are identical or different and represent hydrogen, halogen, trifluoromethyl, hydroxyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl in each case having up to 6 carbon atoms, R¹ represents hydrogen or cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkyl or alkenyl in each case having up to 8 carbon atoms, each of which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, phenyl or a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and/or O, or represents phenyl or a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and/or O, where the ring systems are optionally substituted identically or differently up to 3 times by halogen, phenyl, trifluoromethyl or straight-chain or branched alkyl or alkoxy in each case having up to 5 carbon atoms, hydroxyl or a group of the formula --NR¹¹ R¹², in whichR¹¹ and R¹² have the meaning of R⁹ and R¹⁰ given above and are identical to or different from this, L represents an oxygen or sulphur atom, R² represents mercapto, hydroxyl, straight-chain or branched alkoxy having up to 8 carbon atoms or the group of the formula ##STR170## in which R¹³ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,R¹⁴ denotes hydrogen, phenyl or a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and/or O, R¹⁵ denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxyl, and their salts.
 2. Substituted xanthines of the formula according to claim 1, in whichA represents a radical of the formula ##STR171## in which R³, R⁴, R⁶ and R⁷ are identical or different and denote hydrogen, phenyl, cyclopropyl, cyclopentyl or cyclohexyl, ordenote straight-chain or branched alkyl or alkenyl in each case having up to 6 carbon atoms, each of which is optionally substituted by fluorine, chlorine, bromine, hydroxyl or phenyl, T, V, X and T are identical or different and denote an oxygen or sulphur atom, R⁵ and R⁸ are identical or different and denote hydrogen, fluorine, chlorine, bromine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or straight-chain or branched alkyl or alkenyl in each case having up to 6 carbon atoms, each of which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, naphthyl, phenyl, pyridyl, thienyl or furyl, which can be substituted identically or differently up to 2 times by phenyl, benzyl, fluorine, chlorine, bromine, hydroxyl or straight or branched alkyl or alkoxy in each case having up to 4 carbon atoms, or denote phenyl, pyridyl, thienyl or furyl, each of which is optionally substituted identically or differently up to 2 times by fluorine, chlorine, bromine, phenyl, trifluoromethyl, hydroxyl or straight-chain or branched alkyl or alkoxy in each case having up to 4 carbon atoms or a group of the formula --(CO)_(a) --NR⁹ R¹⁰, in whicha denotes a number 0 or 1, R⁹ and R¹⁰ are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl or acyl in each case having up to 4 carbon atoms, D and E are identical or different and represent hydrogen, fluorine, chlorine, bromine, trifluoromethyl hydroxyl or straight-chain or branched alkyl or alkoxy in each case having up to 4 carbon atoms, R¹ represents hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or straight-chain or branched alkyl or alkenyl in each case having up to 6 carbon atoms, each of which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyridyl or thienyl, or represents phenyl, pyridyl, furyl or thienyl, each of which is optionally substituted identically or differently up to 2 times by fluorine, chlorine, bromine, phenyl, trifluoromethyl or straight-chain or branched alkyl or alkoxy in each case having up to 4 carbon atoms or a group of the formula --NR¹¹ R¹², in whichR¹¹ and R¹² have the meaning of R⁹ and R¹⁰ given above and are identical to or different from this, L represents an oxygen or sulphur atom, R² represents mercapto, hydroxyl, straight-chain or branched alkoxy having up to 6 carbon atoms or the group of the formula ##STR172## in which R¹³ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,R¹⁴ denotes hydrogen, phenyl, pyridyl, furyl or thienyl, R¹⁵ denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl, and their salts.
 3. Substituted xanthines of the formula according to claim 1, in whichA represents a radical of the formula ##STR173## in which R³, R⁴, R⁶ and R⁷ are identical or different and denote hydrogen, phenyl, cyclopropyl, cyclopentyl or cyclohexyl, ordenote straight-chain or branched alkyl or alkenyl in each case having up to 5 carbon atoms, each of which is optionally substituted by fluorine, chlorine, bromine, hydroxyl or phenyl, T, V, X and Y are identical or different and denote an oxygen or sulphur atom, R⁵ and R⁸ are identical or different and denote hydrogen, fluorine, chlorine, bromine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or straight-chain or branched alkyl or alkenyl in each case having up to 5 carbon atoms, each of which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, thienyl or furyl, which can be substituted identically or differently up to 2 times by phenyl, benzyl, fluorine, chlorine, bromine, hydroxyl or straight-chain or branched alkyl or alkoxy in each case having up to 3 carbon atoms, or denote phenyl, pyridyl, thienyl or furyl, each of which is optionally substituted identically or differently up to 2 times by fluorine, chlorine, bromine, phenyl, trifluoromethyl, hydroxyl or straight-chain or branched alkyl or alkoxy in each case having up to 3 carbon atoms or a group of the formula --(CO)_(a) --NR⁹ R¹⁰, in whicha denotes a number 0 or 1, R⁹ and R¹⁰ are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl or acyl in each case having up to 3 carbon atoms, D and E are identical or different and represent hydrogen, fluorine, chlorine, bromine or trifluoromethyl, R¹ represents hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or straight-chain or branched alkyl or alkenyl in each case having up to 5 carbon atoms, each of which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyridyl or thienyl, or represents phenyl, pyridyl, furyl or thienyl, each of which is optionally substituted identically or differently up to 2 times by fluorine, chlorine, bromine, phenyl, trifluoromethyl or straight-chain or branched alkyl or alkoxy in each case having up to 3 carbon atoms or a group of the formula --NR¹¹ R¹², in whichR¹¹ and R¹² have the meaning of R⁹ and R¹⁰ given above and are identical to or different from this, L represents an oxygen or sulphur atom, R² represents mercapto, hydroxyl, straight-chain or branched alkoxy having up to 5 carbon atoms or the group of the formula ##STR174## in which R¹³ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,R¹⁴ denotes hydrogen, phenyl, pyridyl or thienyl, R¹⁵ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by hydroxyl, and their salts.
 4. Substituted xanthines of the formula according to claim 1, in whichA represents a radical of the formula ##STR175## in which R³, R⁴, R⁶ and R⁷ are hydrogen, straight-chain or branched alkyl in each case having up to 4 carbon atoms,T, V, X and Y are identical or different and denote an oxygen or sulphur atom, R⁵ and R⁸ are identical or different and denote hydrogen, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclohexyl or straight-chain or branched alkyl or alkenyl in each case having up to 3 carbon atoms, each of which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, thienyl or furyl, which can be substituted identically or differently up to 2 times by phenyl, benzyl, fluorine, chlorine, bromine, hydroxyl or straight-chain or branched alkyl or alkoxy in each case having up to 3 carbon atoms, or denote phenyl, pyridyl, thienyl or furyl, each of which is optionally substituted identically or differently up to 2 times by fluorine, chlorine, bromine, phenyl, trifluoromethyl, hydroxyl or straight-chain or branched alkyl or alkoxy in each case having up to 3 carbon atoms or a group of the formula --(CO)_(a) --NR⁹ R¹⁰, in whicha denotes the number 0, R⁹ and R¹⁰ are identical or different and denote hydrogen or straight-chain or branched alkyl in each case having up to 3 carbon atoms, D and E are identical or different and represent hydrogen, fluorine, chlorine, bromine or trifluoromethyl, R¹ represents hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, L represents an oxygen atom, R² represents hydroxyl, straight-chain or branched alkoxy having up to 5 carbon atoms or the group of the formula ##STR176## in which R¹³ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,R¹⁴ denotes phenyl, R¹⁵ denotes straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by hydroxyl, and their salts.
 5. Substituted xanthines according to claim 1 wherein such compound is N- 2-(R)-Phenyl-1-hydroxyethane!-2-(R)-cyclopentyl- 4-(1,3-dimethyl)-2,6-dioxo-8-benzyl-1,2,3,6-tetrahydro-purin-7-ylmethyl)phenyl!acetamide of the formula ##STR177## and salts thereof.
 6. Substituted xanthines according to claim 1 wherein such compound is N- 2-(R)-Phenyl-1-hydroxyethane!-2-(R)-cyclopentyl- 4-(1,3-dimethyl)-2,6-dioxo-8-(4-methyl)phenyl-1,2,3,6-tetrahydro-purin-7-ylmethyl)phenyl!acetamide of the formula ##STR178## and salts thereof.
 7. Substituted xanthines according to claim 1 wherein such compound is N- 2-(R)-Phenyl-1-hydroxyethane!-2-(R)cyclopentyl- 4-(1,3-dimethyl)-2,6-dioxo-8-(3-thienyl)-1,2,3,6-tetrahydro-purin-7-ylmethyl)phenyl!acetamide of the formula ##STR179## and salts thereof.
 8. Substituted xanthines according to claim 1 wherein such compound is N- 2-(R)-Phenyl-1-hydroxyethane!-2-(R)-cyclopentyl- 4-(1,3-dimethyl)-2,6-dioxo-8-(2-thienyl)-1,2,3,6-tetrahydro-purin-7-ylmethyl)phenyl!acetamide of the formula ##STR180## and salts thereof.
 9. Substituted xanthines according to claim 1 wherein such compound is N- 2-(R)-Phenyl-1-hydroxyethane!-2-cyclopentyl- 4-(1,3-dimethyl)-2-thiooxo-6-oxo-8-ethyl-1,2,3,6-tetrahydro-purin-7-ylmethyl)phenyl!acetamide of the formula ##STR181## and salts thereof.
 10. A composition for the treatment of atherosclerosis comprising an amount effective therefore of a compound or salt thereof according to claim 1 and a pharmacologically acceptable diluent.
 11. The method of treating atherosclerosis in a patient in need thereof which comprises administering to such patient an amount effective therefore of a compound or salt thereof according to claim
 1. 